TW200808735A - Amino-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compounds for the inhibition of β-secretase - Google Patents

Abstract

The present invention provides a 2-amino-5-[4-(difluoromethoxy)pheny1]-5-3,5-dihydro-phenylimidazol-4-one compound of formula l: The present invention also provides methods for the use thereof to inhibit β-secretase(BACE) and treat β-amyloid deposits and neurofibrillary tangles.

Description

200808735 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to 2-amino-5-[4-(difluorodecyloxy)phenyl]-5-phenyl-3,5-dihydroimidazole -4-ketone compounds and methods of using them to inhibit 0-secretase and to treat β-amyloid deposition and neurofibrillary tangles. [Prior Art] --amyloid and neurofibrillary tangles are two major pathological features associated with Alzheimer's disease (AD). Clinically, AD is characterized by loss of memory, cognition, understanding, judgment, and sense of direction. The development of the disease also affects movement, perception, and language ability until the overall impairment of multiple cognitive functions occurs. These cognitive impairments occur gradually, but usually result in serious injury and eventually die within 4-12 years. Amyloid plaques and vascular amyloid angiopathy are also hereditary cerebral hemorrhage in the brain of patients with Trisomy 21 (Down's syndrome), with Dutch-like amyloid breakdown. (HCHWA-D) and other features of neurodegenerative diseases. Neurofibrillary tangles also occur in other neurodegenerative disorders, including disorders caused by dementia (Varghese, J. et al., Journal of Medicinal Chemistry, 2003, 46, 4625-4630) ° β-amyloid deposition Mainly due to the deposition of Αβ peptide, which is followed by a protein hydrolysate of the amyloid precursor protein (ΑΡΡ). More specifically, at the C-terminus, one or more γ-secretase enzymes and a β-secretase enzyme (BACE) at the Ν-end (also known as aspartame thiol protease) are the pathways for β-amyloid formation. Part of it) causes ΑΡΡ ΑΡΡ to produce Αβ peptide. 114619.doc 200808735 B ACE activity is directly related to the production of Αβ-peptide by APP (Sinha et al., Nature, 1999, 402, 5 37_540), and ongoing studies have shown that inhibition of BACE inhibits Αβ peptide production (Roberds, S. L_ et al., Human Molecular Genetics, 2001, 10, 1317-1324). Accordingly, it is an object of the present invention to provide a compound which is an inhibitor of β-secretase and which can be used for the treatment, prevention or alleviation of elevated β-amyloid deposition or β-amyloid protein characterized by a patient. A therapeutic agent for a disease or disorder. Another object of the present invention is to provide a method of treatment and a pharmaceutical composition for treating, preventing or ameliorating a disease or disorder characterized by elevated β-amyloid deposition or β-amyloid amount in a patient. A feature of the present invention is that the compounds provided can also be used to further study and derive beta-secretase enzymes. These and other objects and features of the present invention will become more apparent from the following description. SUMMARY OF THE INVENTION The present invention provides a compound of the following formula I:

Of which 114619.doc 200808735

Ri and R2 are each independently an alkyl group, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and each group may be substituted as appropriate, or & and r2 may be formed together with the atom to which they are attached, as the case may be. Optionally substituted 5- to 7-membered ring containing an additional hetero atom selected from hydrazine, N or s; R3 is hydrazine or alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each The radicals may be substituted; R4, R5 and R6 are each independently 卤素, halogen, N02, CN, COR7, NR10CO2Rn > NRi5COR16 - ORi4 " NR12Ri3 ' SOnR17^ alkyl, halogen alkyl, dilute, halogen, a fast-radical, cycloalkyl or heterocycloalkyl group, each group optionally substituted, or if attached to an adjacent carbon atom, R4 and R5 may form one or two selected from the group to which they are attached. a heterocyclic atom of N or S, optionally substituted with a 5- to 7-membered ring; η is 0, 1 or 2; and a ruthenium 7 and each independently a ruthenium, NH, or a ruthenium group, a halogen group, an alkoxy group Carboxyl, alkenyl, alkynyl, cycloalkyl or aryl, each group optionally substituted; R8 and R9 are each independently hydrazine or alkyl, alkenyl, alkynyl or cycloalkyl, each group may be Substituting, or & and R9, together with the atom to which they are attached, form a 5- to 7-membered ring, optionally substituted with a hetero atom selected from hydrazine, hydrazine or S;

Ru, "^ and! ^ Each independently is hydrazine or alkyl, _alkyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl, each group optionally substituted; 114619.doc -8 - 200808735

Rio and Ri5 are each independently an alkyl group which is substituted or optionally substituted; and R!2 and R are each independently an alkyl group or a cycloalkyl group, and each group may be substituted as appropriate, or a ruler and a ruler " An optionally substituted 5- to 7-membered ring containing, optionally, a hetero atom selected from hydrazine, hydrazine or S, may be formed with the atom to which it is attached; or a tautomer thereof, a stereoisomer thereof or Pharmaceutically acceptable salts. The invention also relates to the use of such compounds in the treatment of beta-amyloid deposition and neurofibrillary tangles. Formulas are especially useful for the treatment of Alzheimer's disease, cognitive impairment, Down's syndrome, HCHWA-D, cognitive decline, Alzheimer's disease, cerebral amyloid angiopathy, degenerative dementia or other neurodegenerative disorders . [Embodiment] Alzheimer's disease (AD) is a major degenerative disease of the brain, and its clinical phenomenon is the gradual loss of memory, cognition, understanding, judgment, and emotional stability' and will gradually lead to the spirit of depth. Deteriorated and died. The exact cause of Ad is unknown, but evidence of continued increase suggests that amyloid p-peptide (Α-β) plays an important role in the pathogenesis of the disease (DB Schenk; R. E, et al., Journal of Medicinal Chemistry Medicinal Chemistry), 1995, 21, 4141 and D. J. Selkoe, Physiology Review, 2001, 8 1,741). However, patients with AD present a unique neurological condition, such as neuronal plaques (and beta-amyloid white blood vessel disease, deposited in the blood vessels of the brain) and neurofibrillary tangles detected in the brain during autopsy. Α_ρ is the main component of neuroplaques in the AD brain. In addition, ρ_amyloid protein sinking 114619.doc 200808735 and vascular β-amyloid angiopathy are also suffering from Down's syndrome, hereditary cerebral hemorrhage due to Dutch-type amyloid breakdown (Hereditary Cerebral Hemmorhage) And other individuals with neurodegeneration and disorders caused by dementia are characterized. Excessive expression of amyloid precursor protein (APP), cleavage of APP to Α-β or reduction of Α-β from the brain of the patient may increase the solubility or fibrosis of Α-β in the brain. Beta-position cleavage enzyme (BACE1), also known as memapsin-2 or Asp-2, was identified in 1999 (R. Vassar, Β. D. Bennett et al., Nature, 1999, 402, 537). BACE1 is a membrane-bound aspartic protease with all known functional properties and characteristics of β_secretase. Low molecular weight, non-peptide, non-substrate related inhibitors of BACE1 or β-secretase can substantially assist in the study of β-secretase enzymes and as potential therapeutic agents. Unexpectedly, it has now been found that the amine-5-[4-(difluoromethoxy)phenyl]-5-phenylimidazolone compound of formula I demonstrates inhibition of β-secretase and selective inhibition of BACE1 . Advantageously, the phenylimidazolone compound is useful as an effective therapeutic agent for treating, preventing or ameliorating a disease or disorder characterized by elevated amyloid deposition or beta-amyloid levels in a patient. Accordingly, the present invention provides an amine (difluoromethoxy)phenyl]-5-phenylimidazolone compound of the following formula I: 114619.doc -10- 200808735

among them

Ri and R2 are each independently an alkyl group, an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, and each group may be optionally substituted, or 1 and 1^2 may be formed together with the atom to which it is attached. a 5- to 7-membered ring optionally substituted with a hetero atom selected from hydrazine, hydrazine or S; R3 is hydrazine or alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, Each group may be substituted as appropriate; R4, R5 and R6 are each independently Η, halogen, N〇2' CN, COR7, NRi〇C02Rh - NRi5COR16 - 〇R14 . NR12R13 - SOnR17^ alkyl, haloalkyl, alkenyl, Tetraalkenyl, alkynyl, cycloalkyl or heterocycloalkyl, each group optionally substituted, or if attached to an adjacent carbon atom, JU and R5 may form one or two together with the atom to which they are attached Depending on the Ο, N or S heteroatoms, the % is substituted to the 7• member ring; η is 0, 1 or 2; 11? and R” are each independently NR, NRSR9, or a sulphur group or a halogen group. Alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl, each group optionally substituted; 114619.doc -11- 200808735 RAR9 is independently a ruthenium or a diasterium, a dilute, a fast radical or a ring Burning base, Each group may be substituted as appropriate, or R8 and R9 may, together with the atoms to which they are attached, form a 5- to 7-membered ring optionally substituted with a hetero atom selected from the group consisting of hydrazine and N*S;

Rn, each independently H or alkyl, dentyl, alkoxyalkyl, alkenyl, alkynyl, cycloalkyl or aryl, each group being optionally substituted;

Rio and Ri5 are each independently hydrazine or optionally substituted alkyl; and R12&Ru are each independently hydrazine or alkyl or cycloalkyl, each group may be substituted, or R!2&RU may be attached thereto The atoms together form a 5-7 to 7-membered ring optionally substituted with a hetero atom selected from the group consisting of hydrazine, N*s; or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. It is to be understood that these claims cover all possible stereoisomers and prodrugs. Further, unless otherwise stated, each alkyl, alkoxy, alkenyl, alkynyl, nonylalkyl, heterocycloalkyl, aryl or heteroaryl group is contemplated to be substituted as appropriate. The group substituted as appropriate may be substituted with one or more substituents. Substituents which may be present as appropriate may be one or more of the substituents customary for the development of a pharmaceutical compound or to modify the compound to affect its structure/activity, persistence, absorbency, stability or other advantageous properties. Specific examples of the substituent include a halogen atom, a nitro group, a cyano group, a thiocyanate group, a cyanate group, a hydroxyl group, an alkyl group, an alkyl group, an alkoxy group, a haloalkoxy group, an aryloxy group, an amine group, Alkylamino, dialkylamino, fluorenyl, carbonyl, alkoxycarbonyl, carboxy, 114619.doc -12- 200808735 calcined base, thiol group, alkyl sulfinyl group, alkyl sulfonate The base, the amine mercapto group, the alkyl decylamino group, the phenyl group, the phenoxy group, the benzyl group, the benzyloxy group, the cycloalkyl group or the heterocyclic group 'is preferably a halogen atom, a lower alkyl group or a lower alkyl group. An oxy group, wherein "low carbon" is 1 to 4 carbon atoms. In a specific example, the substituent may be selected from a benzyl group, a cyano group, a hydroxyl group, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group or a ring. An alkyl group. Unless otherwise stated, 〇4 substituents may be present. If any of the foregoing substituents represents or contains an alkyl substituent, it may be straight or branched and may contain up to 12 carbon atoms. Preferably up to 6 carbon atoms, more preferably up to 4 carbon atoms. As used herein, the term "alkyl", which contains from 1 to 12 carbon atoms, preferably from 1 to 6 carbon atoms. And branched-chain (unless defined otherwise) monovalent saturated hydrocarbon group of the "better" lower "alkyl of 1 to 4 carbon atoms. Examples of saturated alkyl hydrocarbon alkyl groups include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, t-butyl; High carbon homologues such as n-pentyl, n-hexyl and the like. The alkyl group may be substituted as appropriate. Suitable alkyl substituents include, but are not limited to, CN, OH, halogen, alkenyl, alkynyl, cycloalkyl, phenyl, aminecarboxamyl, carbonyl, alkoxy or aryloxy. As used herein, the term 'haloalkyl group' is referred to as a CnH2n+1 group having 1 to 2n+1 identical or different halogen atoms. Examples of the haloalkyl group include CF3, CI^Cl, C^HsBrCl, C3H5F2 and the like. Similarly, the haloalkoxy group is referred to as QCnH2n+1 having 1 to 2n + 1 identical or different halogen atoms. As used herein, the term "alkoxyalkyl" refers to a court base as defined above substituted with at least one Cl_c4 alkoxy group. As used herein, the term "alkenyl" refers to a straight chain containing at least one double bond and having 114619.doc -13 - 200808735 having 2-12 carbon atoms 'better 2-6 carbon atoms' and preferably 2_4 carbon atoms. Or a branched hydrocarbon group. The hydrocarbon alkenyl group may be mono- or polyunsaturated and may exist in an E or Z configuration. The compounds of the present invention are intended to include all possible and Z configurations. Mono or polyunsaturated hydrocarbons Examples of groups include, but are not limited to, chemical groups such as ethylene, 2-propenyl, isopropyl, croton, 2-isoindole, butadiene, 2-(butadienyl) , 2,4-pentadienyl, 3-(1,4-pentadienyl) and higher carbon homologues, isomers, etc. As used herein, the term "halo" refers to having one or more of the same Or an alkenyl group as defined above with a different halogen atom. As used herein, the term "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. The alkynyl group preferably has 2 to 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl and the like. In some embodiments, an alkynyl group can be substituted with up to four of the above substituents. As used herein, the term "cycloalkyl" refers to a mono-, di-, bi-, fused, bridged or spiro-saturated carbocyclic group of 3 to 1 carbon atoms. Any suitable ring position of the cycloalkyl group can be covalently attached to the defined chemical structure. Examples of decyl groups include, but are not limited to, chemical groups such as cyclopropyl, tert-butyl, cyclopentyl, cyclohexyl, cycloheptyl, borneol, adamantyl, snail [4.5] fluorenyl, And homologues, isomers, and the like. As used herein, the term "heterocycloalkyl" denotes a 5- to 7-membered ring containing i, 2 or 3 of the same or different heteroatoms selected from ruthenium, osmium or S and optionally containing a double bond. Alkyl ring system. Examples of heterocycloalkyl ring systems encompassed by the term herein are those wherein & is <11, 〇 or 8, and R' is oxime or a substituent as defined above. 114619.doc -14- 200808735 ^ ό ^ α As the term is used herein, aryl" represents an aromatic carbocyclic group containing up to 20 carbon atoms, for example 6-20 carbon atoms, which may be a single ring (monocyclic) or polycyclic (double ring system, up to three rings) fused together or covalently linked. Examples of aryl groups include, but are not limited to, chemical groups such as phenyl, quinone-naphthyl, 2-cyanoyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthracenyl, phenanthryl, fluorenyl, A full base, biphenylenyl, acenaphthenyl 'acenaphthylenyl, and the like. In some specific examples, "aryl, can be substituted by 5 substituents. As used herein, the term "heteroaryl" denotes an aromatic heterocyclic ring system having, for example, 5 to 20 ring atoms, which may be a monocyclic ring (monocyclic ring) or a polycyclic ring which is fused together to be covalently bonded ( Bicyclic system, up to three rings. Preferably, the heteroaryl group is 5- to 6-membered. The rings may contain from one to four heteroatoms selected from nitrogen, oxygen or sulfur, wherein the nitrogen or sulfur atom is visible Case oxidative, or nitrogen atom may optionally be quaternized. Examples of the group include, but are not limited to, heterocycles such as decyl, thiophene, pyrrole, pyrazole, imidazole, oxazole, isoxazole, thiazole, iso嗟嗤, 1Η-tetrasaine, lk oxadiazole, triazole, n-heart 3, 2, pyridinium, pyrimidine, pyrazine, pyridazine, benzoxazole, benzoisoxanthene, thiazole, stupid Furan, stupid and thiophene, thiazide, stupid imidazole, eucalyptus, 丨 喧 、, 啥 啥 啥嗤, 啥嗤 啥, 啥 啥 、, σ 呤, σ votes 114619.doc •15- 200808735 pyridine, 9H- Carbazole, α-carboline, etc. As used herein, the term "representative" means fluorine, chlorine, bromine or iodine. The compounds of the present invention can be converted to salts, especially pharmaceutically acceptable salts, using procedures known in the art. Suitable salts with bases are, for example, metal salts such as alkali metal or alkaline earth metal salts, such as sodium, potassium or magnesium salts, or with ammonia or organic amines such as morpholine, thiomorpholine, piperidine, pyrrolidine, single... Or a tri-lower alkylamine such as ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl, tributyl- or dimercaptopropylamine, or single...two Or a salt formed by a trihydroxy lower alkylamine such as mono-, mono- or diethanolamine. An internal salt can also be formed. Also included are salts which are not suitable for medical use but which can be used, for example, for the isolation or purification of a free compound or a salt thereof for use as a salt. As for the term "pharmaceutically acceptable salt" as used herein, when the invention & composition contains an organic group, salts derived from organic and inorganic acids, such as acetic acid, propionic acid, lactic acid, citric acid, Tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrogen acid, acid, nitric acid, sulfuric acid, acid, naphthalene, benzene (four), Τ 姐 sister, camphor acid and similar known acceptable acids. When the compound of the present invention contains a hydroxy acid group or a squaring group or a similar group which can form an addition salt, it may also be a salt formed from an organic or inorganic base, preferably an alkali metal salt such as sodium, lithium or potassium. salt. The compounds of the invention may exist in one or more tautomers. Those skilled in the art will appreciate that the compounds of formula I can also be interconverted as shown below: _ exist: 114619.doc •16- 200808735

Tautomers usually exist in equilibrium with each other. When such tautomers are converted to each other under environmental and physiological conditions, they provide the same useful biological effect. The present invention encompasses mixtures of such tautomers and individual tautomers of compounds of Formula I, It, Ita, Itb, and the like. The compounds of the invention may contain asymmetric carbon atoms and certain of the compounds of the invention may contain one or more asymmetric centers and, therefore, optical isomers and diastereomers may be produced. Although Formula I does not exhibit stereochemistry, the present invention encompasses the optical isomers and diastereomers, as well as racemic and resolved, enantiomerically pure R and S stereoisomers, and R&s Other mixtures of stereoisomers and their pharmaceutically acceptable salts. If a stereoisomer is preferred, in some embodiments it will be provided substantially free of the relevant enantiomer. Thus, an enantiomeric system that is substantially free of related enantiomers refers to a compound that is isolated or isolated by separation techniques, or that is prepared to be free of the relevant enantiomer. As used herein, "substantially free" means that the compound is from a significantly greater proportion, preferably less than about 5%, more preferably less than about 75%, and even more preferably less than about 9%. A stereoisomer consists of a preferred compound of formula I wherein R<R2aH is a compound. Another group of preferred compounds is a compound of the formula: (1_(:4 alkyl). 114619.doc -17- 200808735 Also preferred are those wherein R4, and each of 116 are independently oxime, halogen, COR7, 0R14, or each optionally substituted alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl or cycloalkane More preferably, the compound of the invention is a compound of formula I wherein 1 and 112 are oxime and R3 is methyl. Another group of compounds of the invention are those wherein R4 is ruthenium, COR7, OR14 or each Substituted alkyl, alkyl, alkoxy, haloalkoxy, alkynyl or cycloalkyl; and R5 and 116 are each independently a compound of formula I wherein halo or halogen. In one embodiment, R4 is optionally One or more substituents selected from alkenyl, alkynyl, yl, hydroxy, alkoxy or cycloalkyl. In the present invention, R4 is located at the 3-position of the phenyl ring. Another group of more preferred compounds of the invention are those wherein 1 and 112 are oxime; R3 is fluorenyl; R4 is ruthenium, COR7, ruthenium 14 or each may be substituted An alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl or cycloalkyl group; each of r5 and r6 is independently hydrazine or halogen; and & is a compound of formula I located at the 3-position of the phenyl ring. Preferred compounds of the invention comprise: (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H- Imidazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]_3_methyl-5-phenyl-3,5-dihydro-4H- (6 R)-2-amino-5-(3-bromophenyl)-5-[4-(difluorodecyloxy)phenyl]-3-indenyl-3, 5 -diaza-4 Η - 味哇_ 4 _嗣; (5S)-2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]_3 -methyl-3,5-dichloro-4H-17m嗤-4-嗣; 114619.doc -18- 200808735 (5 ft)-2-amino-5-(3-bromo-4-fluorophenyl) )_5-[4_(difluoromethoxy)phenyl]_ 3_methyl-3,5-diaza-methane-4-oxime; (5 S )-2-amino- 5-(3- Bromo-4-fluorophenyl)-5-[4-(difluoromethoxy)phenyl]_ 3 - _3,5_Dinitro- 4H-P m. Sodium-4-嗣; (5R)-2-amino-5-[4-(difluorodecyloxy)phenyl]-3-methyl-5 -(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]- 3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl ]-5-[3-(3-fluoropropyl)phenyl]_3_methyl_3,5-diaza-copper; 2-amino-5-[4-(difluoromethoxy)phenyl] -5-[3-(3,3-di-propylpropyl)phenyl]-3-methyl 3,5-diox-4 Η _ 〇 〇 -4 -4 嗣; 2-amino-5-[ 4-(difluoromethoxy)phenyl]-5-[3-(4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4indole-imidin-4-one; 2-amino-5-[3-(4,4-difluorobutyl)phenyl]_5-[4-(difluoromethoxy)phenyl]-3 ·methyl-3,5 · two mice -4 Η - miso-4 - class; 2-amino-5-[4-(difluorodecyloxy)phenyl]-5-[3-(2-fluoroethyl)phenyl]-3- Methyl-3,5-diaza- 4Η-mouth ϋ -4--4- I I; 2-amino-5-[3-(2,2-difluoroethyl)phenyl]-5-[4 -(Difluoromethoxy)phenyl]-3-methyl-3,5·di-m- 4Η-. Rice 嗤-4-嗣; 2_amino-5-[4-(difluorodecyloxy)phenyl]indolyl-5-[3·(2,2,2-trifluoroethyl)phenyl] -3,5-diaza-4Η-miso-4-indole; 2-amino-5-[4-(difluorodecyloxy)phenyl]_3_methyl-5-[3-(3, 3,3·trimethylpropyl)phenyl]_3,5-diaza- 4Η-嗦嗤-4-steel; 114619.doc -19- 200808735 2-amino-5-[4-(difluoroantimony) Phenyl]_3_indolyl-5-[3_(4,4,'trifluorobutyl)phenyl]-3,5·diaza_4Η· miso_4_嗣; (5R)-2 -amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]_3_methyl-3,5-dihydro-4H-imid-4-one; (58) 2-amino-5-(3-butylphenyl)_5_[4-(difluoromethoxy)phenyl]_3-mercapto-3,5-diaza-411-17 m嗤_4_ 2-amino-5-[4-(difluoromethoxy)phenylmethylpentylphenyl 3.5-dihydro-4H_^ _4__ ; 2·amino-5-[4-( Difluoromethoxy)phenyl]_3·fluorenyl_5_[3_(2-decylbutyl)phenyl]-3,5-digas-4H-πm嗤-4-嗣; 2-amino group -5-(3-but-3-en-1-ylphenyl)-5-[4-(difluoromethoxy)phenyl b- 3_methyl_3,5_diox- 4H-11 m Salivation 4-嗣; 2-amino-5-[3-(cyclopropylmethyl)phenyl]_5_[4_(difluoromethoxy) Phenyl]-3_methyl-3,5-digas_411-crop-4- steel; 3-(3-{2-amino-4-[4-(difluorodecyloxy)benzene Keb 1-methyl-5-oxo-4.5-dihydro-1H-imidazol-4-yl}phenyl)propanenitrile; (5R)-2-amino-5-[4-(difluoromethoxy) Phenyl μ3·methyl-5_(3-pentyl-4-iso-1-ylphenyl)-3,5-dihydro-4-indole-miso-4·one; (5 8)-2-amino group -5-[4-(difluoromethoxy)phenyl]_3-indolyl_5_(3_pent-4-yl-1-ylphenyl)_3,5-dihydro_411-味峻-4_ Ketone; N-(3-{(4R)-2-amino-4-[4-(difluoromethoxy)phenyl]methyl] oxo-4,5-dihydro-1H-imidazole- 4-yl}phenyl)-2-methoxyacetamide; N-(3-{(4S)-2-amino-4_[4-(difluoromethoxy)phenyl]_! Phytate-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-decyloxyacetamide; 114619.doc -20- 200808735 (5S)-2-Amino- 5-[4_(Difluoromethoxy)phenyl]_3_methyl-5-phenyl-3,5-diaza-4 Η-味11坐-4 -酉同; 2·amino-5- [4-(Difluoromethoxy)phenyl]_5_[3-(4-hydroxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4Η-imidazole 4-ketone; 2-amino-5-[4-(difluoromethoxy)phenyl b-5-[3-(4-hydroxybutyl)benzene ]-3-methyl-3,5-dihydro-4Η-imidazole_4-ketone; 2-amino-5-[4-(difluorodecyloxy)phenyl]_5_[3_(5-fluoropentyl) Phenylmercapto-3,5-dihydro-4indole-imidazol-4-one; 2-amino-5-[4-(difluorodecyloxy)phenyl]_5_[3_(4-fluorobutyl) Phenyl]-3-methyl-3,5-dihydro-4Η-imidazol-4-one; 2-amino-5-[4-(difluorodecyloxy)phenyl]_5_[3_( 6_Fluorohexyl)phenyl]-3_methyl-3,5-dihydro-4Η·σ米嗤-4-one; 2-amino-5-[4-(difluorodecyloxy)phenyl] _5-[3-(4-methoxybutyl)phenyl]-3-methyl-3,5-dihydro-4Η-imidazol-4-one; 2-amino-5-[4-(two Fluoromethoxy)phenyl h5^3_[(lz)_3·methoxyprop-1- 1-pyry-1-yl]benyl-methyl-3,5-dioxin-4H-weijun-4-S Same as; 2-amino-5-[4-(difluorodecyloxy)phenyl]-5-[3_(3-methoxypropyl)phenyl]-3-methyl-3,5-one gas- 4H-mouth rice 嗤-4·嗣; 2-amino-5-[3-(4,4-difluorobutyl)phenyl]·5-[4-(difluorodecyloxy)phenyl]-3 -methyl-3,5-dihydro-4Η-imidazol-4-one; 3-{2-amino-4-['(difluoromethoxy)phenyl]]-methyl_5_oxo · 4,5_ dihydro-1 Η-imidazole _4_yl}-!^propyl decylamine; (1Ε)-3-chloroprop-1-enyl 2,5-two Phenyl sulfone; 2-amino-5-[4-(difluoromethoxy)phenyl]_5_{3_[(2-fluoroethoxy)-methyl 114619.doc -21 - 200808735 yl]phenyl} -3-mercapto-3,5-dihydro-4H-mouth oxime-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]_3_indenyl 3 3 Fluoropropoxy)methyl]phenyl}-3,5-dihydro-4H-miso- 4-_; 2-amino-5-[4-(difluoromethoxy)phenyl b-5_[ 3-((methoxymethyl)phenyl]-3-mercapto-3,5-dichloro-4H-mouth rice sal. 4_嗣; 2-amino-5-[3-(butoxymethyl) Phenyl]_5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dichloro-4Η-σ米唾-4-嗣; 2-amino-5-{ 3-[(cyclopropylmethoxy)methyl]phenyl}_5_[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4Η-π米嗤-4 -ketone; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(ethoxymethyl)phenyl]-3-methyl-3,5-dihydro-4? - saponin-4 ketone; 2-amino-5-[4-(difluoromethoxy)phenyl]_3_methyl-5-[3-(propoxymethyl)phenyl]-3 ,5-dihydro- 4Η-米嗤-4-嗣; 2-amino-5-[4-(difluoromethoxy)phenyl]_5-(3_{[2-fluoro(fluoromethyl)) Lacto]methyl}phenyl)-3-mercapto-3,5-dihydro-411-17嗤-4__ ; 2-amino-5-[4-(difluoromethoxy)phenyl]_3-methyl is _{3_[(2,2,2-trifluoroethoxy)methyl]benzene }}-3,5-dihydro-4H-flavored s--4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]_3_methyl--{3_(2, 2,3,3_tetrafluoropropoxy)methyl}phenyl}-3,5·dihydro·4Η-isoxazol-4-one; 4-[4-(difluorodecyloxy)phenyl] -4-[3·(3-methoxypropio-1_yne-丨-yl)phenyl]-1-methyl-4,5-dihydro-1Η-imidon-2-amine; 2-amine 5-[3-(1,4-difluorobutyl)phenyl]_5_[4_(difluoromethoxy)phenyl]_3_methyl-3,5-dihydro-4Η-imiline- 4-keto; 2-amino-5-[4-(difluoromethoxy)phenyl]-[3_(3-fluorobutene). , olefin ^• base) 114619.doc -22- 200808735 phenyl]-3-methyl_3,5-dihydro-4H-mi. -4-ketone; 2-amino-5-[3-(4,4-difluorobut-3-en-1-yl)phenyl]-5-[4-(difluorodecyloxy)benzene Base]_3_mercapto-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-indolyl-5- [3-(4,4,4-trifluorobutyl)phenyl]_3,5-dihydro-4H_indol-4-one; 5-(3-(2-amino)-4-[4- (difluoromethoxy)phenyl]-1-methyl_5-oxo-455-dihydro-lH-imidazol-4-yl}phenyl)pentanenitrile; 4-(3-{2-amino group -4·[4-(Difluoromethoxy)phenyl]-1.methyloxo-4,5-dihydro-1Η-imidazol-4-yl}phenyl)butyronitrile; 2-Amino- 5_{3_[()-4,4-difluorobut-1-en-1-yl]phenyl}-5-[4-(dioxymethoxy)benzyl]-3-methyl-3 ,5-Dichloro-4-indole; 2-amino-5-[4-(difluoromethoxy)phenyl 5-[3-(3-hydroxyhexyne-yl)phenyl]-3 -methyl-3,5·dihydro-4 fluorene- hydrazin-4-one; 2_amino-5-[4-(difluoromethoxy)phenyl]_5j3_[(1e)_6-methoxy Hexyl-1-en-1-yl]phenyl}-3-methyl-3,5-dihydro-4H-mip-4-one; 2-amino-5_[4-(difluoromethoxy) Phenyl) 1-phenyl-1-yl]phenyl}_3_fluorenyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy) Base) phenyl]_5_{3_[in (曱 曱 )) cyclopropyl]phenyl b 3-mercapto-3,5-dihydro-4 oxime-imidazol-4-one; 2-amino-5-[4_(difluoromethoxy) Stupid base 5-{3_[(1Ε)_5_hydroxypenten-1-yl]phenyl}-3-methyl_3,5-dihydro-4Η-imidazole_4-ketone; 2-amino- 5-[4-(Difluoromethoxy)phenyl]·5_{3_[(1Ε)-3_methoxypropen-1-en-1-yl]phenyl}-3·indolyl-3, 5-dihydro-AH-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy) phenyloxybutane _ 114619.doc -23- 200808735 1-ene-1- Phenyl]-3-methyl-3,5-dihydro-411-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]_5 j3_[( 1E)_4_hydroxybuten-1-yl]phenyl}_3-methyl-3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy) Phenyl]_5_{3_[2_(2-methoxyethyl)cyclopropyl]phenyl}-3-methyl-3,5-dihydromyristin-4-one; 2-amino- 5-(4-(difluoromethoxy)phenylfluorobuty-en-1-yl]phenyl}-3.methyl-3,5-dihydro-4H-imidin-4-one; 2- Amino-5-[4-(difluoromethoxy)phenyl]_5_p-[(1E)-5-fluoropenta-en-1-yl]phenyl}-3-methyl-3,5- Dihydro-4H-normidine-4-one; 5-(3-ethylmercaptophenyl)-2-amino-5-[4-(difluoro Oxy)phenyl]-3-methyl_3,5-dihydro-4-indolizyl-4-one; 2-amino-5-[4-(difluorodecyloxy)phenyl]_5_{4 ·Fluoro-3-[(1Ε)-4-fluorobut-1-ene-1-yl]phenyl}-3-methyl-3,5-dihydro-4Η-imidin-4-one; Amino-5-[4-(difluorodecyloxy)phenyl]_5-[3_(3_fluoropropan-anthracene-2-yl)phenyl]_3_methyl-3,5·dihydro Miso-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hydroxyphenyl)-3-indolyl-3,5-dihydro- 4H_Misin-4__; 2-Amino-5-[4-(difluoromethoxy)phenyl]_5-[3-(3-fluoropropoxy)phenyl]-3-indolyl-3 , 5-dihydro-4H_imidon-4-one; 2-amino-5-[3-(cyclopropyldecyloxy)phenyl]-5-[4-(difluoromethoxy)benzene ]]-3_mercapto-3,5-dihydro-4H-imidin-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl- 5-[3-(4,4,4·Trifluorobutoxy)benyl]_3,5·diaza-; 2-amino-5-indole (2,2-difluoroethoxy)phenyl ]-5-[4_(difluoromethoxy) 114619.doc -24- 200808735 Phenyl]-3-methyl-3,5-dihydro-4H-miso-4-one; 2-amino- 5-[4-(difluoromethoxy)phenyl]_5_[3-(4-fluorobutoxy)phenyl b-3-methyl-3,5-diaza-411_ 口米°坐-4 2-amino-5-[4-(difluoromethoxy)phenyl]_3__methyl-5-[3_(3-phenoxypropoxy)phenyl]_3,5_2 Hydrogen-4H-11 methane-4-S is the same; 4-(3-{2-amino-4-[4-(difluoromethoxy)phenyl) 1-methyl-5-oxo_ 4 ,5-dihydro-1H-imidazol-4-yl}phenoxy)butyronitrile; 2-amino-5-[4-(difluoromethoxy)phenyl]-5_[4_fluoro-3_( 3_Fluoropropoxy)phenyl]-3-indenyl·3,5·dihydro-4H-miso-4-_; 2·amino-5-[3-(but-2-yne-1 -yloxy)_4_fluorophenyl]_5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4Η-imidon-4-one; 2-amine 5-[4·(Difluoromethoxy)phenyl]_5_[4-fluoro-3_(4-fluorobutoxy)phenyl]-3-methyl-3,5-dihydro-4Η- 11 m嗤-4-_ ; 2-amino-5-[3-(2,2-difluoroethoxy)_4_fluorophenyl]_5_[4-(difluorodecyloxy)phenyl]_3 _methyl_3,5-dihydro-4Η-mouth rice 嗤4· ketone; (5R)-2-amino _5-[4-(difluoromethoxy)phenyl]_5_[4_fluoro -3_(3_Fluoropropyloxy)phenyl]-3-methyl-3,5-dihydro-4H-miso-4-_; (5S)-2-amino-5-[4-( Difluoromethoxy)phenyl]_5_[4_fluoro_3 gas fluoropropyloxy)phenyl]-3-methyl_3,5-dihydro-4H-miproxen-4-enone; 2- Amine _5-{3_[ (4,4-difluorobut-3-en-1-yl)oxy]phenyl b-[4-(difluoromethoxy)phenyl]_3_methyl·3,5-dihydro-4H -imidazol-4-one; (5S)-2-amino-5-[3-(2,2·difluoroethoxy)_4_fluorophenyl]_5_[4-(difluoromethoxy)benyl] 3-methyl-3,5·dihydro-4Η·miso-4-one; (5R)-2-amino-5-[3-(2,2-difluoromethoxy)_4_fluoro Phenyl]_5_[4_(二114619.doc -25-200808735 methoxy)phenylmethyl-hydrogen-hydrogen-octavalent-ketone; 2-amino-5-[4-(difluoromethoxy) Phenyl is arsenic ethyl) phenyl] winter methyl-3,5-dihydro-4 oxime-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl ]_5例5_气气戍)Phenyl]_ 3-methyl-3,5-dihydro·4Η_flavor-4-one; 2amino-5·[4-(monofluoromethoxy) )phenyl]|[3♦ butyl aryl) phenyl 3-methyl-3,5-dihydro-4H-flavor. Sit; 2_Amino-5-[3-(butyl-3-dil-diyloxy)phenylindole methoxy)phenyl]-3-methyl_3,5-dihydro- 4H-imidapy-4-_; 2-amino-5-[3-(but-3-enyloxy)_4_fluorophenyl]_5_[4-(difluoromethoxy)phenyl]- 3-methyl-3,5-dihydro-4H-imidazole-4-one; (5R)-2-amino-5-[3-(but-3-en-1-yloxy)phenyl] _5·[4_(difluoromethoxy)phenyl]_3_methyl-3,5-dihydro-4Η_imipine_4_one; (5S)-2-amino-5-[3-( But-3-en-1-yloxy)phenyl]_5-[4·(difluoromethoxy)phenyl]-3-mercapto-3,5-dihydro-411-imidazole- 4-ketone ; 2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]_4_fluorophenyl b-5 [4-(difluoromethoxy) Phenyl]-3_methyl_3,5-dihydroimidazolidinone; 2-amino-5-[4-(difluorodecyloxy)phenylphenyl)-3-methyl·3,5 Dihydro-4Η-imidol-4-one; 2_amino-5-(3-but-3-en-1-yl-4-fluorophenyl)·5-[4-(difluoromethoxy) Phenyl]-3-methyl-3,5-dihydro-411-miso-4-_; 3-{2-amino-4-[4-(difluoromethoxy)phenyl 1-methyl_5_oxo_4,5-dihydro-1H-imidazole-4-yl}benzaldehyde; 2-amino-5-[4-(difluoromethoxy)phenyl]_5-[ 3-(1- Keto-2-yne-1 - 114619.doc -26- 200808735 phenyl)-3-mercapto-3,5-dihydro-4H-imidazol-4-one; amine 5 [4 ( _fluoro曱oxy)phenyl]-5-[3-(1,4-di-dibutylbutyryl-2-yl)-1-yl]-3-methyl_3,5-dihydro-4H-imidazole- 4-ketone; (5R)-2-amino-5-[3_(difluoromethoxy)phenyl]_5_[4-(difluoromethoxy)phenyl]-3_methyl_3,5- Dihydro-4H-imidazol-4-one; 2 monoamino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2,2-dimethyl-3-oxo Cyclobutyl)phenyl]_3-methyl-3,5-dihydro-4H-imidazole-4-one; 2amino-5-[4-(difluorodecyloxy)phenyl]_3_methyl _5_[3_(3_oxocyclobutyl)benyl]-3,5-dihydro-4H-flavor-4-one; 2-amino-5-[4-(difluoromethoxy) Phenyl]·5·[3_(3-hydroxycyclobutyl)phenyl]-3-methyl-3,5-dihydro_4Η-σ米嗤—4-one; [3-(3-{2 -Amino_4_[4_(difluoromethoxy)phenyl]-imethyl_5-oxo-4.5-dihydro-l-indole-imidazole-4-yl}phenyl)cyclobutyl]acetic acid methyl ester; 3-(3-{2·Amino-4_[4-(difluorodecyloxy)phenylbupromethyl_5_oxo-4.5-dihydro-1Η-imidazol-4-yl}phenyl)cyclobutylene Methyl acetate; or its tautomers, Isomer thereof or a pharmaceutically acceptable salt thereof. More preferred compounds of the invention comprise: (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]_3_methyl_5_phenyl·3,5_diox-4H-p (5R)_2-amino-5·[4_(difluoromethoxy)phenyl]_3-methyl-5-(3-pent-4-en-1-ylphenyl -3,5·dihydro-4H-mito-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]_3_methyl-5-( 3-propion_ι_ fast-1 basic base)_3,5-two mice-4 Η _味σ sit 4 _嗣; (5 feet)-2_amino-5-[4-(dimethoxymethoxy) Phenyl]_3-methyl_5-(3-pent_1_114619.doc -27- 200808735 fast-1 - basic group)-3,5-two-rat-4 Η_11 m saliva-4-嗣; 5R)-2_Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3·(3-methylbut-1-an-1-yl)benzene (3R)-2-amino-5-[4-(difluorodecyloxy)phenyl]_5-[3-(3-曱oxyprop-1--1-yn-1-yl)phenyl]·3_methyl- 3,5-diindole-4H-味峻_4-_ ; (5)-2-amino-5- [4-(Dimethoxy)phenyl]-5-[3-(4-methoxybut-1-n-1-yl)phenyl]-3-indenyl-3,5-dihydro -4H-flavor. -4-ketone; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentanes-1-yl)phenyl]- 3-methyl_3,5-dihydro-4H-m-methane-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5-{ 3-[(3S)_3-hydroxybutan-1-dry-1-yl]benyl-methyl- 3,5-dichloro- 4H_ 米米吐_4_纲; (5R)-2-amino- 5-[4-(Difluorodecyloxy)phenyl]-5-[4-fluoro-3-(3-methoxyprop-1·yn-1-yl)phenyl]-3-indenyl- 3,5-dihydro-4H·m-methane-4-one; (5R)-2-amino[5-[4-(difluoromethoxy)phenyl]_5-[4-fluoro_3·( 4_decyloxybut-1-yn-1-yl)phenyl]-3-methyl-3,5-dihydro-4-indole-4-one; (5R)-2-amino-5 -[4_(difluorodecyloxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3-indenyl-3,5-dihydro-4H-port Rice bran-4·ketone; (5R)-2·amino-5-[3-(2,2-difluoroethoxy)-4•fluorophenyl]-5-[4·(two-gas emulsion) Base)-3-yl-3,5-diox-4 Η _味σ sit-4 - 酉; (5R)-2-amino _5_{3·[(4,4-two Fluorin-3-ene-1-yloxy]phenyl b-5_[4-(«-fluoromethyllacyl)benzyl]-3-methyl-3,5-dichloro-4Η-flavor 0 sitting - 4-3⁄4 ; or its mutual variants, its three-dimensional Configuration or a pharmaceutically acceptable salt thereof. The compounds of formula I can be prepared using conventional synthetic methods and, if desired, standard separation or isolation techniques. For example, a compound of formula I can be obtained by reacting a diketone of the formula 与 with an amine hydrazine derivative of the formula m in the presence of a base such as a metal carbonate to obtain the desired compound of formula 114619.doc -28-200808735. This reaction is shown in the following Scheme i.

Flowchart I

The diketone compound of formula II can be obtained by reacting an alkyne of formula IV with an oxidizing agent such as Pd(II)Cl/DMSO, N-bromosuccinimide/DMSO, ozone, hydrazine (IV) oxide hydrate-containing sodium periodate Prepared by reacting sulfur trioxide, ΚΜη04, I2/DMSO or a combination thereof (preferably ΚΜη04 and I2/DMSO). This reaction is shown in Scheme II below.

Flowchart II

The alkyne compound of the formula IV can be obtained by reacting an ethynylbenzene compound of the formula V with a Pd catalyst such as dichlorobis(triphenylphosphine)palladium(II) and Cul with 4-(difluoromethoxy)-1_ It is prepared by reacting iodobenzene to obtain the desired phenylethynylbenzene compound of the formula IV. This reaction is shown in Scheme III below. 114619.doc -29- 200808735

Flowchart III r5

(V) j0-OCHF2

PdCI2(PPh3)2

Cul, Et3N, DMF

Preferably, the compound of formula I is used as a treatment and disease such as Alzheimer's disease, trisomy 21 (Down's syndrome), hereditary cerebral hemorrhage due to Dutch-type amyloid breakdown (HCHWA-D) and BACE inhibitors for β-amyloid deposition and neurofibrillary tangles associated with other neurodegenerative diseases. Accordingly, the present invention provides a method for regulating, preventing or alleviating diseases and disorders such as Alzheimer's disease, trisomy 21 (Down's syndrome), due to Dutch-type amyloid breakdown. Hereditary cerebral hemorrhage (HCHWA-D) and other methods of neurodegenerative disorders associated with amyloid deposition and neurofibrillary tangles. Such methods generally comprise administering an effective amount of a compound of formula I to a patient who is expected to have or has suffered from a disease or injury associated with excessive BACE activity. According to the present invention, there is provided a method of treating Alzheimer's disease and related Alzheimer's disease in a human or other mammal, the method comprising administering to a human or other mammal an effective amount of a compound of the present invention. The invention also provides a method of treating a condition associated with or caused by excessive boce activity in a subject in need thereof, the method comprising administering to the patient a therapeutically effective amount of at least one compound of the formula. Representative diseases include Alzheimer's disease, cognitive impairment, Down's syndrome, hchwa_d, recognition 114619.doc -30- 200808735 scalp retreat 'Alzheimer's disease, greatly fine-winning vascular disease, degenerative dementia or Other neurodegenerative disorders. This particular disease is characterized by the production of beta-amyloid deposits or neurofibrillary tangles. The invention also provides a method of inhibiting bribe activity, comprising administering to a patient or contacting the receptor with an effective amount of a compound of formula I. A method is also included to determine μ(3) activity before or after the contacting step. The invention also provides a method of alleviating a mammalian stimulating protein-like protein deposit or a fibril fibrillation. The method comprises administering to the mammal an effective amount of at least one compound of formula I. The present invention also provides for alleviating Alzheimer's disease, cognitive impairment, Down's syndrome, HCHWA_D, cognitive decline, Alzheimer's disease, cerebral dysplasia, degenerative dementia or other neurodegeneration in mammals. Method of dysregulation' The method comprises administering to the mammal an effective amount of at least one compound I. % Step: The method of preventing Alzheimer's disease, cognitive impairment, Down syndrome, HCHWA D, 4 knowledge decline, Alzheimer's disease, brain hall for mammals who are known to be at risk of suffering from various diseases Powdery vascular disease, degenerative dementia or other neurodegenerative disorders. Such methods comprise providing an effective amount of at least one of the compounds in the mammal as a conjugate. As used in the present invention, and in the context of providing a compound or substance encompassed by the present invention, "for " means directly administering the compound or substance, or administering an effective amount of the compound or substance in vivo. A drug, derivative or analogue. The invention also contemplates the provision of a compound of the invention for the treatment of such conditions as described herein using such compounds. 114619.doc -31 _ 200808735 The term "a patient" as used herein refers to a mammal, preferably a human. # As for the term "application", "volume &" or "administration" Means direct administration of a compound or composition to a patient, or administration of a compound derivative or analog to a compound which will form an equivalent amount of the active compound or substance in the patient. As for the term "effective amount" as used herein ",", "therapeutically effective amount" "effective dose" means that the administration of a compound to a patient may at least partially alleviate (and preferably cure) the symptoms that may have been affected by the patient. It should be understood that the effective dose of the compound of the present invention may vary depending on the particular compound used, the mode of administration, the symptoms and the severity of the symptoms to be treated, and the various physiological factors of the individual (4) to be treated. For the treatment of Alzheimer's disease and other related Alzheimer's disease, 'usually can be administered at a daily dose of about 500 mg/kg body weight, preferably divided into two to six times a day' or continuously. The released form gives satisfactory results to the patient in need of the compound of the present invention. For the maximum Wei animal, the total dose is about 3.5 mg to about 14 mg, and the car is about 35 to about 5 Mg. The right 70 kg adult's total daily dose is usually about 7 mg to about mg' and can be adjusted to provide the best treatment outcome. The intake can be adjusted to provide the best therapeutic response. The present invention relates to a composition comprising one or more compounds of formula I and one or more pharmaceutically acceptable carriers. The invention also provides a pharmaceutical composition comprising a compound of formula I above and a pharmaceutically acceptable carrier 114619.doc -32- 200808735 The term "carrier" as used herein shall include carriers, excipients, and diluents. Examples of carriers are those known to those skilled in the art and are based on acceptable medical procedures. Preparations are described, for example, in Remington, s Pharmaceutical Sciences, 17th Edition, edited by Alf〇noso r. Gennaro, Mack Publishing Company, (10), PA (198 5), which is incorporated herein by reference in its entirety. The carrier is compatible with the other ingredients of the formulation and is biologically acceptable. The compounds of the invention may be administered orally or parenterally, either neat or in combination with conventional pharmaceutical carriers. One or more substances which can also be used as flavoring agents, lubricants, dissolving agents, suspending agents, fillers, slip agents, compression aids, binding agents or tablet disintegrating agents or encapsulating materials. , for example, formulated in a similar manner to known antihypertensive agents, diuretics, and beta-blockers. Oral formulations containing the active compounds of the invention may include any of the conventional oral forms, including lozenges, capsules, and buccal Dosage forms, tablets, flat tablets and oral liquids, suspensions or solutions. In the case of a powder, the carrier is a fine solid which is premixed with the finely divided active ingredient. In the case of a tablet, the active ingredient is mixed in a suitable ratio with a carrier having the desired compression properties and compressed into the desired shape and size. Powders and lozenges preferably contain up to 99% of the active ingredient. The capsules may contain the active compound with inert fillers and/or diluents such as pharmaceutically acceptable amphoteric starch (for example corn, potato or tapioca starch), cane toad, artificial sweeteners, powdered cellulose such as crystalline and microcrystalline cellulose. , a mixture of flour, gelatin, glue, and the like. Usable tablet formulations can be prepared by conventional compression, wet or dry granule method H4619.doc -33-200808735 and using pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including Preparation of surfactants, suspending agents or stabilizers, including but not limited to magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl Cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, carboxymethylcellulose oxime, polyvinylpyrrolidine, alginate, gum arabic, guar gum, citric acid, composite citrate, Calcium carbonate, glycine, sucrose, sorbitol, dicalcium silicate, calcium sulfate, lactose, kaolin, mannitol, sodium vaporification, low melting point soil and ion father resin. Preferred surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, f-ammonium chloride, calcium stearate, whale butterfly hard decyl alcohol, cesium polyethylene glycol (cet〇macr〇g〇l) Emulsified bismuth, sorbitan ester, colloidal cerium oxide, phosphate, sodium lauryl sulfate, magnesium aluminum silicate and triethanolamine. Oral formulations herein may employ standard delayed or released formulations to modify the absorption of the active compound. The oral formulation may also comprise administering the active ingredient in water or fruit juice, and may contain a suitable solubilizing or emulsifying agent as desired. Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and liquors. The active ingredient of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as dissolving swords, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity adjusting agents, stabilizers or osmotic pressure. Adjust 蜊. Suitable examples of liquid carriers for oral and parenteral administration include water 114619.doc -34 - 200808735 (especially containing the above additives such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including Unit alcohols and polyols, such as glycols and their derivatives, and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and myristic acid /, propyl sulfonate. The sterilized liquid I and the carrier are used in a sterile liquid composition for parenteral administration. The liquid carrier of the pressurized composition can be a toothed tobacco or other pharmaceutically acceptable propellant. Liquid pharmaceutical compositions which are sterile solutions or suspensions can be used, for example, intramuscularly intraperitoneally or subcutaneously. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in liquid or solid form. Preferably, the pharmaceutical composition is in unit dosage form such as a troche, a capsule, a powder, a solution, a suspension, a liquid, a fine granule or a suppository. The composition of the dosage form is divided into unit doses containing a suitable amount of the active ingredient, such as a powder, a vial, an ampoule, a prefilled or a liquid containing pouch. The unit dosage form can be, for example, a capsule or lozenge itself, or any such composition in a suitable number of packages. The unit dosage form can contain from about 1 mg/kg to about 250 mg/kg and can be provided in a single dose or in two or more doses. The dosage can be administered by any of the methods used herein to direct the active compound of the invention to the recipient's blood, including oral, invasive, parenteral (including intravenous, intraperitoneal, and subcutaneous injection), rectal, vaginal, and transdermal administration. Such administration can be carried out using the present compound or a pharmaceutically acceptable salt thereof in the form of a lotion, a cream, a foam, a patch, a suspension, an emulsion, and a suppository (rectal or vaginal). When administered to treat or inhibit a particular condition or disorder, Lai knows the effective 114619.doc -35- 200808735 dose will vary with the particular compound used, the mode of administration, its symptoms and the severity of the condition to be treated' and the individual to be treated It varies with various physiological factors. In therapeutic applications, the compounds of the invention provide an amount sufficient to provide a disease in a condition sufficient to ameliorate or at least partially alleviate the signs of the disease and its complications. The appropriate amount to achieve this is defined as, the therapeutically effective amount, and the dosage used to treat a particular condition must be subjectively determined by the attending physician. The variables involved include specific symptoms and the size, age and mode of response of the patient. In some cases, τ can require direct administration of the compound to the respiratory tract in the form of an aerosol. For intranasal or intrabronchial administration, the compounds of the invention may be formulated as aqueous solutions or as partial aqueous solutions. The compounds of the invention may be administered parenterally or intraperitoneally. A solution or suspension of such active compounds of the free or pharmaceutically acceptable salts can be prepared by suitably mixing in water with a surfactant such as (tetra)propylcellulose. Oily dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof. Under the general conditions of storage and use, such preparations contain a preservative to inhibit the micro-weekly use of a sterilizing aqueous solution or dispersion in a pharmaceutical form for injection and a sterile powder for the preparation of a sterile injectable solution or dispersion. All conditions: This form must be sterilized and must be fluid that is easy to inject. It must be: System =: stable under storage conditions and must be preserved under the action of antimicrobials such as anti-fine. The carrier can be a solvent or dispersion medium containing, for example, a = glycerol, propylene glycol, and liquid polyethylene glycol, a suitable second thereof, and a vegetable oil. The compounds of the present invention can be administered transdermally using a transdermal patch. It should be revealed 114619.doc

-36 - < S 200808735 For purposes, transdermal administration is understood to include all administrations through the body surface and the inner layers of the body passages containing epithelial and mucosal tissues. The administration can be carried out using a parent compound or a pharmaceutically acceptable salt thereof, a coffee, a cream, a foam, a patch, a suspension, a solution, and a suppository (rectal and vaginal). Transdermal administration can be achieved by the use of an active compound-containing compound which is non-toxic to the skin and which is capable of systemic absorption of the transdermal drug into the blood. The carrier can be in any number of forms such as creams and ointments, pastes, gels, and occluding devices. Creams and ointments can be either oil-in-water or water-in-oil viscous liquids or semi-solid emulsions. A paste composed of an active ingredient-dispersed powder dispersed in petroleum or hydrophilic petroleum is also suitable. A variety of occluding devices can be used to release the active ingredient into the blood, such as a semi-permeable membrane or a parent material containing the active ingredient, which contains the active ingredient-containing reservoir with or without the carrier. Other occlusion devices are known in the literature. The compounds of the invention may be administered rectally or vaginally in the form of conventional suppositories. The suppository formulation can be made from conventional materials, including cocoa butter (with or without the addition of wax to alter the suppository's melting point) and glycerin. Water-soluble suppository bases such as polyethylene glycols of various molecular weights can also be used. In some embodiments, the invention relates to prodrugs. Various forms of prodrugs are known in the art, for example, Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder et al. (eds.), Methods in Enzymology, Volume 4 , Academic Press (1985); Krogsgaard_LarSen et al. (eds.), "Design and Application of Prodrugs", Textbook of Drug Design and Development, 114619.doc -37- 200808735

Chapter 5, 113-191 (1991); Bundgaard et al., Journal of Drug Deliver reviews, 8: 1-38 (1992); Bundgaard, J. Pharmaceutical Sciences (J·〇f Pharmaceutical Sciences) , 77:285 et seq. (1988); and Higuchi and Stella (editor) as Prodrugs as Novel Drug Delivery Systems, as described in the American Chemical Society (1975), the full disclosure of each document This article is for reference. It is to be understood that the dosage, ingestion and mode of administration of such compounds will vary depending on the disease and individual to be treated and will be judged by the participating physician. Preferably, one or more of the compounds herein is administered at a low dose at the beginning of the administration and is gradually increased until the desired effect is achieved. For a clearer understanding and to more clearly illustrate the invention, specific examples are set forth below. The following examples are illustrative only and are not to be construed as limiting the scope of the invention and its principles. All parts are by weight unless otherwise stated. The terms TEA, DMSO and DMF are triethylamine, dimercaptoarthracene and N,N-dimethylformamide, respectively. The terms EtOAc and THF are respectively ethyl acetate and tetrahydrofuran. The term NMR is proton nuclear magnetic resonance, and the noun MS is mass spectrometry and (+) refers to the positive mode, which is usually expressed as M+1 (or M+H) absorption, where M = molecular mass. All compounds were analyzed by at least MS and NMR. The proton nuclear magnetic resonance spectroscopy was obtained on a 61:11]^1 八\^\>1 €£3 00 spectrometer at 3 〇 0 MHz or on a VARIAN 4 〇〇 spectrometer at 4 〇〇 mHz. The spectral system is represented by ρριη(δ), and the coupling constant j value is recorded as Hertz. Tetramethyl decane was used as an internal reference standard. Mass spectrometry is at 114619.doc -38 - 200808735

Obtained on Perkin Elmer Sciex 100. Example 1 (5S)-2-Amino-5-[4-(dimethoxymethoxy)-phenyl]·3-methylphenyl_3,5-diaza-4H-imidazol-4-one [ A] and (5R)_2-amino-5-[4-(difluoromethoxy)-phenyl]-3-methyl-5-phenyl-3,5-dihydro- 4H-flavored saliva- Preparation of 4__[b]

Step a) 1-(Difluoromethoxy)-4-(phenylethynyl#yl)benzene is introduced into acetylene containing acetylene (1·9 g, 18.5 mmol), 丨_(diox a mixture of methoxy)-4-iodobenzene (5 g, 18.5 mmol), N,N-dimethylformamide (35 liters) and triethylamine (12.8 ml, 92.6 mM) It lasted 5 minutes. Next, copper iodide (1.85 mmol, 351 mg) and dichlorobis(triphenylphosphine)palladium (11) (1.11 mmol, 71.71 g) were added to the mixture, and the new mixture was allowed to Stir at 60 ° C for 3 hours. The mixture was allowed to cool to room temperature, poured into water and extracted with diethyl ether. The organic extract was dehydrated with MgS〇4. Evaporation and use of hexane/Et0Ac (丨00/1) as a solvent solvent on the silica gel, 114619.doc >39-200808735, to obtain 1-(difluoromethoxy)_4_(benzene) as a clear oil Ethyl ethynyl) benzene (3.45 g 'yield 76%). MS m/e M+244; NMR (400 MHz, DMSOd6) δ 7.2 (d, 8.78 Hz, 2H), 7.28-7.45 (m, 4H), 7.5-7.55 (m, 2H), 7.6 (d, 7.78 Hz , 2H). Step b) ^[4-(Difluoromethoxy)phenyl]-2-phenylethane-1,2-dione in 1-(difluoromethoxy)-4-(phenylethynyl) A mixture of benzene (2.85 g, 11.68 mmol) and dimethyl sulfoxide (4 mL) was introduced with anhydrous argon for 5 minutes. Next, bis(acetonitrile)dichloropalladium (π) (116*mol, 〇.3 g) was added to the mixture, and the new mixture was stirred at 145 ° C for 20 hours. The mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic extract was dehydrated with MgS〇4. Evaporation and purification on phthalocyanine (ISC oxime) using hexane / EtOAc (30 / 1) as a solvent to give a clear oily bismuth. 1,2-dione (2.92 g, yield 91%). MS m/e M+ 276; lH NMR (400 MHz, DMSOd6) δ 7.2 (d3 J = 8.78

Hz, 2H), 7.6 (m, 3H), 7.75 (t J = 8.54 Hz, 1H), 7.88 (d, J = 8.54 Hz, 2H), 7.98 (d, 8 · 78 Hz, 2H). Step c〇2-Amino_5_[4-(difluoromethoxy)phenyl-3-methyl-5-phenyl-3,5-dihydro-4H-carin-4-one in 1- [4_(Fluorodecyloxy)phenyl]-2-phenylethene-oxime, 2·dione (3·7 g, 13.43⁄4 mol), Ershi (180 ml) and EtOH (240 ml) A mixture of 1-methyl pulmonate (6.6 g, 60·3 mmol) and Na 2 C03 (6.4 g, 60.3 mmol) in Ο 2 Ο (20 mL) was added. The new mixture was stirred at 95 C for 3 hours. The volatiles were then removed in vacuo and the residue was taken in water andEtOAc. The organic extract was dehydrated with MgS 4114619.doc -40 - 200808735. Purification by evaporation and purification on EtOAc (EtOAc) (EtOAc/EtOAc (EtOAc) 5--5-phenyl-3,5-diin-4-indole-imidazol-4-one (3.65 g, 94 〇/〇). MS m/e (Μ+Η)+ 332; 4 NMR (400 MHz, DMSOd6) δ 2.93 (s, 3 Η), 6.61 (brs, 2 Η), 7.1 (d, J = 8·54 Ηζ, 2 Η), 7.15 -7.31 (m, 4H), 7.38 (m, 2H), 7.42 (d5 J = 8·54 Hz, 2H). Step d) (5S)-2-Amino-5-[4-(difluoromethoxy)-phenyl-3-methyl-5-phenyl-3,5-dihydro-4H-imidazole-4 -ketone [A] and (5R)-2_amino-5-[4-(difluoromethoxy)"-phenyl]-3-methyl-5phenyl-3,5-diaza_4H - miso-4-嗣[B]

2-Amino-5-[4-(difluorodecyloxy) was carried out by chiral chromatography (Chiralcel OJ, 0.46 x 10 cm, using 85% ethanol with 85% hexane and diethylamine as mobile phase). Separation of the racemic mixture of phenyl]-3-indolyl-5-phenyl-3,5-diaza·4Η-^嗤-4-嗣 to obtain the two enantiomers in white solid; [A] (5S)- 2-Amino-5-[4-(di-m-methoxy)-phenyl]-3-indenyl-5-phenyl-3,5-dihydro-4H-imidazol-4-one, MS m/e </ RTI> </ RTI> <RTIgt; 15_7.31 (m, 4Η), 7·38 (m, 2Η), 7.42 (d, 8·54 Hz, 2H); [a] 25 = +20 (C = 1% in MeOH); and [ B] (5R)-2-Amino- 5-[4-(di-f-methoxy)-phenyl]-3-methyl-5-phenyl-3,5-dihydro-4H-mouth saliva -4·ketone, MS m/e (M+H)+ 332; h NMR (400 MHz, DMSOd6) δ 2·93 (s, 3H), 6.61 (brs, 2H), 7·1 (d, J = 8·54 Hz, 2H), 7.15-7.31 (m, 4H), 7·38 (m, 2H), 7.42 (d, /= 8.54 Hz, 2H); [a] 25 = -22 (C = 1%) In MeOH) 〇 114619.doc -41 - 200808735 Example 2 (5R)-2-Amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3 -Preparation of methyl-3,5-dihydro-4H-imidazol-4-one

The procedure is basically the same as in Example 1, step ad, and in the step a, 2-amido-5-(3-&gt;odorophenyl)-5-[4- (Difluoromethoxy)phenyl]-3-mercapto-3,5-dihydro-4H-imidazol-4-one and subjected to chiral chromatography (Chiralcel OJ, 2x25 cm, using 5% ethanol) 95 ° / hexane and diethylamine as mobile phase were separated to give the title enantiomer, MS m / e (M + H) + 332; lU NMR (400 MHz 5 DMSOd6) δ 2.94 (s5 3H) 5 6.72 ( Brs, 2H), 7.1 (d, J = 8.66 Hz, 2H), 7.13 - 7.35 (m, 2H), 7.38 · 7.43 (m, 4H), 7.56 (t, 1.72 Hz, 1H); [a] 25 = -4 (C = 1% in MeOH). Example 3 (5)-2-amino-5-(3-exyl-4-phenyl)-5-[4-(difluoromethoxy)phenyl]-3_methyl-3,5- Dihydro-411-miso-4-one 114619.doc -42- 200808735

Using essentially the same procedure as described in Example 1, step a, and using 2-bromo-4-a-l-ethyl-bromobenzene' to obtain 2-aminosole-4-phenylphenyl)-5-[4-( a mixture of difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one, and used by chiral chromatography (Chiralcel OJ, 0.46 χ 10 cm, Separation of the title enantiomer, MS m/e (M+H) + 332; ), 6.74 (brs, 2H), 7·1 (d, 8·75 Hz, 2H), 7.13-7.65 (m, 5H), 7.67 (d, /= 2.2 Hz, 1H); [a]25 = - 22 (C = 1% in MeOH). Example 4 (5R)-2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H -imidazol-4-one [A] and (5S)_2.amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3, Preparation of 5-dihydro-4H-imidazol-4-one [B] 114619.doc -43 - 200808735

I-^^-ochf2

1) PdCI2(PPh3)2

l|l SiMe3 2) Cs2C03l CH2CI2, MeOH 1) PdCI2(PPh3)2 Cul, Et3N, DMF

Cul, Et3N, DMF -^

Step a) 2-(3-ethynylphenyl)-l,3-dioxolane in acetylene (trimethyl)decane (36 g, 367 mmol), 2-(3-bromobenzene) ))-1,3-dioxolane (78 g, 342 mmol), N,N-dimethylformamide (400 ml) and triethylamine (1.181 ml, ?mole) The mixture was purged with anhydrous argon gas for 5 minutes, with copper iodide (0.94 g, 4.96 mmol) and dioxobis(triphenylphosphine)palladium (11) (7.7 g, 11.01 mmol). The mixture was stirred at 60 ° C for 3 hours, cooled to room temperature, poured into water and extracted with diethyl ether. The combined organic extracts were dried with EtOAc EtOAc (EtOAc m.) (Trimethyl) decane (63 g, 256 mmol). The yellow oil was dissolved in MeOH (600 mL) and CH.sub.2 C.sub.2 (600 mL). Extract with ether. The combined ether extracts were dehydrated with MgSO4, EtOAc (EtOAc m.). MS m/e M+ 174; ]H NMR (400 MHz? DMSOd6) δ 3.9- 4·05 (m, 4H), 4.15 (s, 1H), 5.7 (s, 1H), 7.35-7.45 (m, 4H) . Step b) 2-(3-{[4_(Difluoromethoxy)phenyl]ethynyl}phenyl) 4,3-dioxolane was used in essentially the same procedure as described in Example 1 Step a, Further, 2-(3-ethynylphenyl)-1,3-dioxolane and hydrazine-(difluoromethoxy)-4-iodobenzene were used to obtain a coupled product. This product was purified on silica gel (ISC®) using hexane/Et〇Ac 5/1 as solvent. 1,3-dioxolane (7·9 g, yield 85%) ^ MS m/β (M+H)+ 317; ^ NMR (400 MHz, DMSOd6) δ 3.9-4.05 (m , 4H), 5·72 (s, 1H), 7.1-7.3 (m, 3H), 7.4 (m, 2H), 7·5_7·6 (m, 4H). Step c) 3-{[4-(Difluoromethoxy)phenyl]ethynyl}benzaldehyde in 2-(3-{[4-(difluoromethoxy)phenyl]ethynyl)phenyl) To a mixture of hydrazine, % dioxolane (1.0 g, 3.1 mmol) and THF (5 mL) was added HCl (2 N '1 mL). The mixture was stirred at room temperature for 2 hours, poured into water and extracted with EtOAc /EtOAc. The organic extract was dehydrated with MgS〇4. Evaporation and purification on cerium (ISC®) using hexane/Et〇Ac (3/i) as the dissolving solution 114619.doc -45-200808735 to obtain 3-{[4-(difluoromethoxy) as a yellow oil Phenyl]ethynyl}benzoic acid (3.65 g, yield 95%), MS m/e M+ 272; NMR (400 MHz, DMSOd6) δ 3.9-4.05 (m, 4H), 5.72 (s, 1H ), 7.1-7.3 (m, 4H), 7.62 (m, 2H), 7·8·7·9 (m, 2H), 8.03 (s, 1H), 9.99 (s, 1H). Step d) Nf-[(lE)_(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzene continued to be ugly with 3 -{[4-(Difluoromethoxy)phenyl]ethynylbenzaldehyde benzaldehyde (3·69 g, 13.573⁄4 mol), 4-methylbenzophenone (2.9 g, 15.6 mmol) and

The mixture of EtOH (ll liter) was refluxed for 3 hrs, cooled to room temperature, poured into water and extracted with diethyl ether. The combined organic extracts were dried with MgSO4 and concentrated in vacuo. The resulting residue was purified on a EtOAc (EtOAc) eluting elute Phenyl]ethynyl}phenyl)methylene]-4-mercaptophthalein (5.4 g, yield 90%), MS m/e (M+H)+ 441; 4 NMR (400 MHz, DMSOd6 ) δ 2.32 (s, 3H), 7·2 (d, 8.66 Hz, 2H), 7·3_7·6 (m, 8H), 7·72 (d, 8·3 Hz, 2H), 7.88 (s, 1H), 11·54 (s, 1H). Step e) (Difluoromethoxy)phenyl]ethynyl propyl benzene is treated with diethyl ether (1.0 Μ in THF, 1.52 mL, ι·52 mmol) containing hydrazine, _[(ιΕ)_( 3] [4_(Difluoromethoxy)phenyl]ethynyl}phenyl)methylene]-4-methylbenzene 醯肼 (〇·67 mg, 1.52 mmol) of the thF mixture, stirring 2 The mixture was treated with NaOH (2.5 mL, EtOAc········ The combined organic extracts were dried over MgSO.sub. The obtained 114619.doc -46-200808735 residue was purified on silica gel (ISCO) using hexanes / EtOAc (50 / 1) as solvent to afford 1-{[4-(difluoromethoxy)benzene as a clear oil. Ethynyl}- 3-propylbenzene (386 mg, yield 89%), MS m/e (M+H)+ 286; 4 NMR (400 MHz, DMSOd6) δ 0.85 (t, J = 7.32 Hz5 3H)5 1.57 (m,2H),2·6 (t,7·32 Hz,2H),7·2 (m,3H),7.35-7.45 (m, 4H), 7.58 (d, 8.79 Hz, 2H ). Step f) difluoromethoxy)phenyl]_2_(3-propylphenyl)ethane q,, diketone

The diketone product was obtained using essentially the same procedure as described in Example 1, step b, and using &lt;[&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; The product was purified on silica gel (ISCO) using hexanes/EtOAc 30/1 as solvent eluting to afford 1-[4-(difluoromethoxy)phenyl]-2-(3-propylphenyl) as a yellow oil. Ethylene-1,2-dione (yield 82%), MS m/e (M_H) + 3 17; 4 NMR (400 MHz, DMSOd6) δ 0.85 (t, 7.32 Hz, 3H), 1.57 (m, 2H), 2.6 (t5 J= 7.32 Hz, 2H)5 7.35 (d, 8.78 Hz, 2H), 7.4-7.5 (m5 3H), 7.65-7.7 (m, 2H), 7.95 (d, /= 8.78 Hz, 2H). Step g) 2-Amino-5-[4-(difluoromethoxy)phenyl-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazole- The 4-ketone was used in essentially the same procedure as described in Example 1, Step C, and using 1_[4_(monofluoromethoxy)phenyl]-2-(3-propylphenyl)ethene. A ketone to obtain a urea-bearing urea product. The product was purified on silica gel (ISCO) using hexane / MeOH 20/1 as elution to afford white solid 2-aminodifluoromethoxy)phenyl]-3-methyl-5- (3-prop. Phenyl)_3,5-dihydro-411_imidazole_4_one (yield 91%), MS m/e (M+H)+ 374; 4 NMR (400 MHz, DMSOd6) δ 0.85 (t, / = 7·2 Hz, 3H), 1·44 (m, 2H), 2.45 (m, 114619.doc -47- 200808735 2H), 2·93 (s, 3H), 6.6 (brs, 2H), 7.0 ( d, J = 7.2 Hz, 1H), 7.06 (d, 8.4 Hz, 2H), 7.1-7.3 (m, 4H), 7.4 (d, 8·54 Hz, 2H). Step h) (5R)-2-Amino-5-[4-(difluorodecyloxy)phenyl]_3_methyl_5_(3-propylphenyl)-3,5-dihydro-4H- Imidazole _4-ketone [A] and (5S)-2-amino-5-[4-(di-m-methoxy)phenyl]-3-indenyl-5-(3-propylphenyl)-3 ,5-Di-argon- 4H-味峻-4-嗣[B] by palm chromatography (Chiralcel OJ, 0.46x10 cm, using 20% ethanol in C02 (100 bar) and diethylamine as mobile phase) Separation of 2-amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4indole-imidazole-4 - a racemic mixture of ketones to give the diastereomer: [A] (5R)-2-amino-5-[4-(difluorodecyloxy)phenyl]-3-methyl-5-(3 -propylphenyl)-3,5-dihydro-4H-imidazol-4-one, MS m/e (M+H). 374; 4 NMR (400 MHz, DMSOd6) δ 0.85 (t, J = 7.2 Hz5 3H)5 1.44 (m 2H), 2.45 (m5 2H), 2.93 (s, 3H), 6.6 (brs, 2H), 7.0 (d, /= 7.2 Hz, 1H), 7.06 (d, J = 8.4 Hz5 2H), 7.1-7.3 (m5 4H), 7.4 (d5 J = 8.54 Hz, 2H); [a] 25 = +28 (C = 1% in MeOH); and [B] (5S)-2_amino -5-[4-(Difluoromethoxy)phenyl]-3-methyl-5-(3-propylphenyl)-3,5-dihydro-4H-imidazol-4-one; MS τη /e (M+H)+ 37 4; lH NMR (400 MHz, DMSOd6) δ 0·85 (t, J = 7.2 Hz, 3H), 1.44 (m 2H), 2.45 (m, 2H), 2.93 (s, 3H), 6·6 (brs , 2H), 7.0 (d, 7.2 Hz, 1H), 7.06 (d, J = 8·4 Hz, 2H), 7.1-7.3 (m, 4H), 7.4 (d, J = 8.54 Hz, 2H); a]25 = -26·6 (C = 1% in MeOH) Example 5 (5R)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy) Phenyl]-3-methyl 114619.doc -48- 200808735 base-3,5-dihydro-4H-imidazol-4-one [A] and (5S)-2-amino-5-(3-butyl Preparation of phenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one [B]

Br MeNHOMe, N people ^VB"PrM9Br

(iPr)2NEt, CH2C\2^ /6 THF NHoNHo KOH, diglyme

Ochf2

OCHF2

PdCI2(PPh3)2 Cul, Et3N, DMF

Step a) 3-Bromo-N-methoxy-N-methylbenzamide is treated with N-methoxyfluorene as CH2C12 containing 3-bromobenzylidene chloride (15 g, 68·5 mmol) A mixture of the alkylamine hydrochloride (22.1 g, 228.5 mmol), diisopropylethylamine (63.5 mL, 365.6 mmol) and CH.sub.2 C. The resulting residue was dispersed in water and extracted with diethyl ether. The combined organic extracts were dehydrated with MgS04 and concentrated in vacuo. The resulting residue was purified on EtOAc (EtOAc) elute elute elut Indoleamine (15.1 g, yield 90%). Step b) 1-(3-Bromophenyl)butan-one was treated with 3-bromo-N-methoxymethylbenzamide, 12.3 g of propylmagnesium bromide (6.15 mL, 12-3 mmol). The mixture was stirred with THF EtOAc (EtOAc) EtOAc. The combined organic extracts were dried with MgSO4 and evaporated. The residue was purified on EtOAc (EtOAc) eluting eluting %). Step c) 1-Bromo-3-butylbenzene treated with hydrazine (1.49 g, 44 mmol) containing 1-(3-bromophenyl)butanone (1.0 g, 4.4 mmol) and diethylene glycol A mixture of dimethyl ether (10 ml) was stirred at 1 ° C for 2 h, treated with hydrazine (1·23 g, 22 mmol), and stirred at 15 0 C for 6 hours, cooled to room temperature. Pour into water and extract with ether. The combined organic extracts were dried with EtOAc EtOAc. The residue was purified on EtOAc (EtOAc) eluting eluting elut elut elut elut elut Step d) 1-Butyl-3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene was used in essentially the same procedure as described in Example 1 Step a, and using 丨_____ butyl Benzene and 1-(difluoromethoxy)-4-ethynylbenzene give the phenylethynylbenzene product. The product was purified on EtOAc (EtOAc) elute elute elute elut ), MS m/e M+ 3 00; lU NMR (400 MHz 5 DMSOd6) δ 0.82 (t, J = 7.19 Hz, 3H), 1.25 114619.doc -50 - 200808735 (m, 2H), 1_55 (m, 2H) , 2.56 (t, "/= 7.56 Hz, 2H), 7·2 (m, 3H), 7.35-7.45 (m, 4H), 7·58 (d, 8·79 Hz, 2H) 〇Step e) 1 -(3-Butylphenyl)-2-[4.(difluoromethoxy)phenyl]ethane 4,2-dione was used essentially in the same procedure as described in Example 1, step b, and using butyl butyl- 3-{[4-(Difluorodecyloxy)phenyl]acetylene}benzene affords the diketone product. The product was purified on silica gel (ISCO) using hexane/EtOAc 30/1 as solvent eluting to afford 1-(3-butylphenyl)-2-[4-(difluoromethoxy)benzene as yellow oil. Ethyl bromide-1,2-diindole (0.39 g, yield 92%), MS m/e (M+H)+ 331; lR NMR (400 MHz, DMSOd6) δ 0.84 (t5 J = 7.32 Hz? 3H), 1.26 (m, 2H), 1.51 (m, 2H), 2.63 (t, J = 7.56 Hz, 2H), 7.35 (d5 8.78 Hz, 2H) 5 7.4-7.5 (m, 3H)5 7.65-7.7 (m5 2H), 7.95 (d, 8.78 Hz, 2H). Step f) 2_Amino-5_(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-amid The 4-ketone was used in substantially the same manner as described in Example 1, Step c, and 1-(3-butylphenyl)-2-[4-(difluoromethoxy)phenyl]-ethane-1 was used. , 2-dione, obtaining the product of beta-urea urea. The product was purified on silica gel (ISCO) using EtOAc/MeOH 20/1 eluting solvent to afford white solid 2-amino-5-(3-butylphenyl)-5.[4-(difluoromethoxy) Phenyl]-3-methyl-3,5-dihydro·4Η-imidon-4-one, MS/e (M+H)+ 388; 4 NMR (400 MHz, DMSOd6) δ 0.82 (t , J = 7.32 Hz, 3H), 1.25 (m 2H), 1.45 (m, 2H), 2.48 (m, 2H), 2.93 (s, 3H)? 6.6 (brs, 2H), 7.0 (d, J = 7.44 Hz? 1H), 7.1 (d, J = 8.78 Hz, 2H), 7.12-7.32 (m, 4H), 7.4 (d, /= 8.78 Hz, 2H). Step g) (5R)-2-Amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)benzene 114619.doc -51 - 200808735 Keb 3-methyl- 3,5-dihydro-4H-imidazole·4-one [A] and (5S)_2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)benzene Keb 3-methyl-3,5-dihydro-4H-imidazol-4-one [B] by palm chromatography chromatography [Chiralcel OJ, 0.46x10 cm, using 20% ethanol in C02 (100 bar) and Diethylamine as mobile phase] Separation of 2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-di Hydrogen-4H-imidazol-4-one, obtaining two enantiomers: [A] (5R)-2-amino-5-(3-butylphenyl)-5-[4-(difluoromethoxy) Phenyl]-3-mercapto-3,5·dihydro-4H-imidazol-4-one; MS m/e (M+H)+ 388; 4 NMR (400 MHz, DMSOd6) δ 0.82 (t5 J = 7.32 Hz, 3H), 1.25 (m 2H), 1.45 (m, 2H), 2.48 (m, 2H), 2.93 (s, 3H), 6.6 (brs, 2H), 7.0 (d5 J = 7.44 Hz, 1H), 7.1 (d, J = 8.78 Hz, 2H)5 7.12-7.32 (m, 4H), 7.4 (d, = 8_78 Hz, 2H); [a]25 = +25 (C = 1% MeOH); and [B] (5S)-2·amino-5-(3-butylphenyl)-5-[4-(dimethoxymethoxy)phenyl]·3-methyl-3, 5_ dihydro-4H-mi Zyzol-4-one, MS m/e (M+H)+ 388,4 NMR (400 MHz, DMSOd6) δ 0·82 (t,··= 7·32 Hz, 3H), 1·25 (m 2H ),1·45 (m,2H), 2.48 (m,2H),2·93 (s,3H),6.6 (brs,2H),7.0 (d, J = 7.44 Hz, 1H), 7.1 (d, J = 8.78 Hz, 2H), 7.12-7.32 (m, 4H), 7.4 (d, 8.78 Hz, 2H); [a] 25 = -28.8 (C = 1% in MeOH). Example 6-10 2-Amino-5-[4-(difluorodecyloxy)phenyl]-3-methyl-5-(3-substituted phenyl)_ 3,5-dihydro_4H_ The imidazole-4 ketone compound was prepared using essentially the same procedure as described in Example 5, step df, using 1-114- phenylbenzene and 1-(di- methoxy) as appropriate 114619.doc-52-200808735 -4 -ethylidene)benzene, the compound shown below was obtained and confirmed by HNMR and mass spectrometry. Example 6: 2·Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pentylphenyl)-3,5-dihydro-4H-imidazole -4-ketone

MS m / e (M + H) + 402; lU NMR (400 MHz 5 DMSOd6) δ 0.72 (t, J = 6.83 Hz, 3H), 1·22 (m 4H), 1.44 (m, 2H), 2.48 (m) , 2H), 2.93 (s, 3H), 6.6 (brs, 2H), 7.0 (d, /= 7·08 Hz, 1H), 7.1 (d, "/= 8.66 Hz, 2H), 7.12-7.32 (m , 4H), 7.4 (d, 8·66 Hz, 2H) 〇 Example 7: 2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-[3- (2-methylbutyl)phenyl]-3,5-diargon-4H-imidazole-4·one

MS m/e (M+H)+ 402; lU NMR (400 MHz, DMSOd6) δ 0.7 (d5 J = 6.58 Hz, 3H), 0·78 (t, 7·45 Hz, 3H), 1.05 (m, 1H), 1.24 (m,1H), 1.48 (m,1H), 2.23 (m,1H), 2.51 (m,2H),2·93 (s,3H),6.61 (brs,2H),7.0 (d , 7_07 Hz, 1H), 7·1 (d, J = 8·54 Hz, 2H), 7.12-7.32 (m, 4H), 7·4 (d, 8.54 Hz, 2H). Example 8: 2-Amino-5-(3-but-3-en_1-ylphenyl)-5-[4-(difluoromethoxy)benzyl]-3-methyl-3,5 -diaza-4H - miso·4_嗣114619.doc -53· 200808735

MS m / e (M + H) + 386; lU NMR (400 MHz, DMSOd6) δ 2.2 (m5 2H), 2.58 (m, 2H), 2.93 (s, 3H), 4·9 (m, 2H), 5.8 (m, 1H), 6·6 (brs, 2H), 7.8 (m, 3H), 7·1·7·25 (m, 4H), 7.4 (d, 8.79 Hz, 2H). Example 9: 2-Amino-5-[3-(cyclopropylmethyl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5·2 Argon-4H-imidazol-4-one

MS m / e (M + H) + 386; lU NMR (400 MHz, DMSOd6) δ 0.08 (m, 2H), 0.38 (m, 2H), 0.87 (m, 1H), 2.41 (d, = 6.96 Hz, 1H), 2.93 (s, 3H), 6.6 (brs, 2H), 7.04 (d, 8.67 Hz, 2H), 7.1-7.3 (m, 5H), 7.44 (d, 8.67 Hz, 2H). Example 10: 3-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]_1-methyl-5-oxo-4,5-diar-1H-imidazole- 4-yl}phenyl)propionitrile

MS m / e (MH) + 383; lU NMR (400 MHz, DMSOd6) δ 2.7 (m5 2H), 2.8 (m, 2H), 2.93 (s, 3H), 6.62 (brs, 2H), 7.05 (d, 8.66 114619.doc -54- 200808735

Hz, 2H), 7.15 (m, 2H), 7.21 (t, J = 7.45 Hz, 1H), 7.3 (m, 2H), 7.43 (d, J = 8.66 Hz, 2H) o Example 11 (5R)-2 _Amino-5-[4-(difluorodecyloxy)phenyl]_3. fluorenyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro-4H- Imidazole _4_ ketone [A] and (5S) 2 -amino _5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3_pent-4_ene_1- Preparation of phenyl)_3,5-dihydro-4H-imidazolone [B]

Br νΗ2ΝΗ2

1) Mg, THF

Br 2) ΚΟΗ, diglyme

Palm separation

Ochf2

Step a) 1-(3-Bromophenyl)pent-4-en-1-one was treated dropwise with magnesium (0.48 g, THF) containing (bromomethyl)cyclopropane (2.49 g, 18.45 mmol). A mixture of 20.29 millimoles of THF was heated at reflux temperature for 1 hour and poured into 3-bromo-N-methoxy-N-methylthionamide (2 5 114619.doc -55 - 200808735 g, 10.24 m The mixture was cooled to room temperature and stirred for 1 hr. and quenched with aqueous NH4C1 and extracted with diethyl ether. The combined organic extracts were dried with EtOAc EtOAc. The residue was purified on EtOAc (EtOAc) elute elute elut elut elut elut elut elut MHz, DMSOd6) δ 2.3 (m, 2H), 3.1 (t, J = 7.19 Hz, 2H), 5.02 (m, 2H), 5.8 (m, 1H), 7.47 (t5 J = 7.93)

Hz5 2H)5 7.77 (dd5 J= 7.08, 2.2 Hz), 7.94 (dd5 J= 7.81, 1.58 Hz), 8.04 (t, J = 1.83 Hz, 1H). Step b) 2-Amino-5-[4-(difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-ylidene-1-ylphenyl)-3, 5-Dihydro-4H-sneeze_4_one was used in essentially the same procedure as described in Example 5, step df, and using ι_(3_bromophenyl)pent-4-en-1-one and hydrazine (difluoro) Methoxy)-4_ethynylbenzene, 2-amino-5-[4-(difluorodecyloxy)phenyl]_3_methyl_5_(&gt;pent-4-enyl base)- 3,5·1H-HHHHHHH^H/HNMR (400 MHz, DMSOd6) δ 21.6 (m, 2H), 1.9 (m, 2H), 2.5 (m, 1H) ), 2.93 (s, 3H), 4.9 (m, 2H), 5.78 (m, 1H), 6.6 (brs, 2H), 7-7.08 (m, 3H), 7.1-7.3 (m, 4H), 7.4 ( d, 8·67 Hz, 2H). Step c) (5R)-2-Aminodifluoromethoxy)phenyl]_3-methyl·5_(3_pent-4-en-1-ylphenyl)-3,5-dihydro_4Η- Imidazole _4-ketone [Α] and (5S)-2_amino-5-[4-(difluoromethoxy)phenyl]_3_methyl-5-(3-pent-4-ene_1 _Phenylphenyl)-3,5-dihydro-4H-imidol-4-one [B] by palm chromatography (Chiralpak AD, 0.46x25 cm, using 10% ethanol in 90% hexane and two Separation of 2_amino group by ethylamine as mobile phase_5_[4_(2114619.doc -56-200808735 (difluoromethoxy)phenyl]-3-indolyl-5-(3-pent-4-ene) A racemic mixture of -1-ylphenyl)-3,5-dihydro-4H-imidazol-4-one affords two enantiomers: [A] (5R)_2-Amino-5-[4- (Difluoromethoxy)phenyl]-3-methyl-5-(3-pent-4-indol-1-ylphenyl)-3,5-dihydro-411-mouth rice 嗤-4-_ , MSm/e(M+H)+400, !H NMR (400 MHz? DMSOd6) δ 21.6 (m5 2H)? 1.9 (m? 2H)3 2.5 (m,1H), 2.93 (s,3H), 4.9 (m, 2H), 5.78 (m, 1H), 6.6 (brs, 2H), 7-7.08 (m, 3H), 7.1-7.3 (m, 4H), 7.4 (d, 8.67 Hz, 2H); ]25 = +23 (C = 1% in MeOH), and [B] (5S)-2-amino- 5-[4-(difluoromethoxy)phenyl]-3-methyl-5- (3•penten-1-ylbenzene ,3,5-dihydro-4H-imidazole. , 2H), 2·5 (m, 1H), 2·93 (s, 3H), 4.9 (m, 2H), 5.78 (m, 1H), 6·6 (brs, 2H), 7-7.08 (m , 3H), 7.1-7.3 (m, 4H), 7.4 (d, "/= 8.67 Hz, 2H); [a] 25 = -19 (C = 1% in MeOH) o Example 12 N-(3-{ (4R)-2-amino-4-[4.(difluoromethoxy)phenyl]-i-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl} Phenyl)_2-methoxyacetamide [A] and N-(3-{(4S)-2-amino-4_[4·(difluoromethoxy)phenylpi-methyl_5_ Preparation of oxo_4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamidine [B] 114619.doc -57- 200808735

I

OCHF2

OCHF2 PdCI2(PPh3)2 -&gt; Cul, Et3N, DMF

KMN04, NaHC03 -► ~ MgS04, Acetone, H20

Step a) 3-{[4-(Difluoromethoxy)phenyl]ethynyl}aniline using essentially the same procedure as described in Example 1, step a, and using 3-ethynylaniline and 1- (two gas) Oxy)-4-mothene benzene affords the phenylethyl carbamide product. The product was purified on silica gel (ISCO) using EtOAc / hexanes 1/3 as solvent. ), MS m/e (M+H)+ 260; 4 NMR (400 MHz, DMSOd6) δ 5_26 (brs, 2H), 6·6 dd (, J = 8.17, 2·31 Hz, 1H), 6· 67 (dd, 7.44, 2.43 Hz, 1H), 6.72 (d, J = 2·4 Hz, 1H), 7.05 (t, J = 7.81 Hz, 1H), 7·43 (d, J = 6.1 Hz) , 2H), 8.55 (d, J = 6.1 Hz, 2H) 〇Step b) N-(3-[{4-(Difluorodecyloxy)phenyl}ethynyl]phenyl)-2-methoxy Acetamine 114619.doc -58 - 200808735 3-{[4-(fluorofluoromethyl)phenyl]ethynyl group was treated dropwise with methoxyethyl hydrazine chloride (0.5 g, 4.63 mmol) Benzylamine (1 g, 3.86 mmol), triethylamine (〇·65 ml, 4·63 mmol) of CH2C12 was cooled (0. 〇 solution, allowed to return to room temperature, stirred for 2 hours, poured The mixture was extracted with EtOAc / EtOAc / EtOAc (EtOAc)EtOAc. Yellow solid Ν-(3·[{4-(difluoromethoxy)phenyl}ethynyl]phenyl)_2-methoxyacetamide (1·25 g, yield 94%), MS m/ e (M+H)+ 332; lR NMR (400 MHz? DMSOd6) δ 3.30 (s, 3H)? 3.97 (s, 2H), 7.2 (m, 3H), 7.3 (m, 2H), 7.6 (m, 3H), 7.9 (t, / = 1·7 Hz, 1H), 9.84 (s, 1H). Step c) N_{3-[[4-(Difluoromethoxy)phenyl](oxo)B N-(3_[{4_(difluoromethoxy)benyl}ethynyl]benzene was treated with 苯基ηΟ4 (0·32 g, 2.05 mmol) with phenyl]-2-methoxyacetamide. ))-2-methoxyacetamide (〇·68 g, 2.05 mmol), acetone, H20, NaHCO3 (0.1 g, 1.25 mmol) and MgS〇4 (0.37 g, 3.07 mmol) A mixture of the ears was stirred at room temperature for 4 Torr and filtered. The filtrate was diluted with water and extracted with a puzzle. The combined organic extracts were dried over MgSO.sub. The residue was purified on a silica gel using hexane/EtOAc (1/1) as eluting solvent to afford N-{3-[[4-(trifluoromethoxy)phenyl](oxo)醯基]phenyl bromide 2-methoxyacetamide (0.73 g, yield 98%), MS m/e (M+H)+ 364; NMR (400 MHz, DMSOd6) δ 3·32 (s, 3H), 3.96 (s, 2H), 7·34 (d, / = 8-91 Hz, 2H), 7.5-7.6 (m, 3H), 7.97 (d, 8.91 Hz, 2H), 8.05 114619.doc - 59- 200808735 (dd,7·81,1·7 Hz,1H), 8.27 (t,ΐ·7 Hz,1H),1〇〇6 (s, 1H) 〇Step d) N-(3-{2 -amino-4-[4-difluoromethoxy]phenylmethyl-5-oxo-4,5.dihydro-1H-imidazol-4-yl)phenyl)_2-methoxyacetamidine The amine was used essentially in the same procedure as described in Example 1, step c, and using N_(3_[[4-(difluoromethoxy)phenyl](oxo)ethenyl]phenyl}_2_methoxy B The indoleamine was obtained as the product of the indoleamine. The product was purified on silica gel (ISC) using EtOAc/MeOH 10/1 as solvent to afford white solid (3_{2-amino-4-[4-( Difluoromethoxy)phenylmethyl_5-oxo·4,5-dihydro-1Η-imidazol-4-yl}phenyl)-2-methyl Ethyl amide (0.15 g, yield 7 〇%), MS m/e (M+H) + 419; lH NMR (400 MHz, DMSOd6) δ 2.93 (s, 3H), 3.30 (s, 3H), 3.90 (s,2H),6·61 (brs,2H),7.08 (m,3H), 7.2 (m5 2H)5 7.44 (d3 J = 8.78 Hz5 2H)5 7.55 (d5 J = 7.93 Hz5 1H), 7.62 (s, 1H), 9.71 (s, 1H) 〇Step e) N_(3_{(4R)_2·Amino_4-[4_(difluoromethoxy)phenyl i methyl_ 5-oxo · 4,5-Di-argon-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide as a chiral chromatographic technique (Chiralcel AD, 2 x 25 cm, using 25% isopropanol 75 °/〇hexane and diethylamine as mobile phase) Separation of N_(3-{2-Amino-4-[4-^*曱曱oxy]yl}}indolyl-5-oxo- A racemic mixture of 4,5-diaza-1H-hydroxy-saltyl-4-yloxy-2-yloxyacetamide to obtain a white solid of two enantiomers: [A] N-(3 -{(4R)-2_Amino-4-[4-(difluorodecyloxy)phenyl]indolyl_5_oxo-4,5·dihydro·1Η_imidazol-4-yl}phenyl )-2-methoxyacetamide, MS m/e (M+H) + 419; lU NMR (400 MHz, DMSOd6) δ 2.93 (s5 3H)? 114619.doc -60- 200808735 3.30 (s, 3H ), 3.90 (s, 2H), 6.61 (brs, 2H), 7.08 (m,3H), 7.2 (m, 2H), 7.44 (d5 8.78 Hz, 2H)? 7.55 (d? J= 7.93 Hz? 1H)5 7.62 (s,1H), 9.71 (s,1H); a]25 = +18 (C = 1% in MeOH); and [B] N-(3-{(4S)-2-amino-4-[4-(difluoromethoxy)phenyl]- 1-Methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxyacetamide, MS m/β (M+H)+ 419; lU NMR (400 MHz? DMSOd6) δ 2.93 (s5 3H)? 3.30 (s, 3H), 3.90 (s, 2H), 6.61 (brs, 2H), 7.08 (m, 3H), 7.2 (m, 2H)? 7.44 (d5 J= 8.78 Hz5 2H)5 7.55 (d? J = 7.93 Hz, 1H)5 7.62 (s,1H), 9.71 (s,1H); [a]25 = -16 (C = 1% in MeOH ). Example 13 2·Amino-5-[4-(difluoromethoxy)phenyl]_3_methyl-5-[3·(4,4,4-tris-butyl)phenyl]-3,5 -Preparation of dihydro-4Η-imidazol-4-one

Br ΝΗ2ΝΗ2 [ΚΟΗ, diglyme

114619.doc -61 · 200808735 Step a) 3-Bromo-N-methoxymethylbenzylamine A solution of 3-bromobenzamide (2 gram, 9 ΐ·ι mmol) in CH2Cl2 was added dropwise. Cooling with CH2Cl2 containing N,0-dimethylhydroxylamine hydrochloride (33.6 g, 319 mmol), diisopropylamine (98 mL, 551 mmol) (〇.〇 solution) After 1 hour, stirring was continued for 3 hrs at room temperature, followed by concentration in vacuo. The obtained residue was taken in water and evaporated with diethyl ether. The organic extracts were combined, dried with EtOAc and concentrated in vacuo. Purification using hexane/EtOAc (4/1) as a solvent to afford pale-yellow solid scent of N-decyloxy-N-methyl decylamine (2 g, yield 89%), (M) +H) + 244. H NMR (4GG MHZ, DMSO-d6) δ ppm, 3.21 (s, 3H), 3·50 (s, 3H), 7.37-7.39, (m, 1H), 7.53-7.55 (m , 1H), 7.64-7.66 (m, 1H), 7·67-7·69 (m, 1H). Step b) l-(3·Bromo-phenyl&gt;4,4,4-trifluoro-butyl - ketone δ-fluoromethylethane-magnesium bromide (made in § 丨 with 丨 · bromine, 2-trifluoromethylethane in THF for 2 hours, 4 6 g = 25. 8 2 mM) 制备 ρ preparation solution was slowly added to a solution containing 3-bromo-N-methoxy-N-methylbenzylamide (3.5 g 14.3 mmol) in THF cooled (〇 ° C) solution Stirring was continued for 1 hour at room temperature, the reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Purification by using hexane/EtOAc (10/l) as a solvent to give a colorless oily oily phenyl-phenyl)-4,4,4-difluoro-butanone (31 g, yield 77%) (μ_ή)_ η H NMR (400 MHz, DMSO-^6) δ ppm5 2.5-2.6 (m, 2 H)5 3.3- 3.4 (m, 2 H), 7.5 (t, "/=7.9 Hz, 1 H ), 7.8-7.8 (m, 1 H), 7.9-8.0 114619.doc -62- 200808735 (m,1 Η),8·1 (t,J=1.7 Hz,1 Η) 〇Step c) 1-Bromo -3-(4,4,4-trifluoro-butyl)-benzene is treated with hydrazine monohydrate (5_5 g, 11 〇·3 mmol) containing ^(, bromo-phenyl)-4,4 , a mixture of 4-trifluoro-but-1-one (3.1 g, U mmol) and diglyme, and stirred at 10 (TC for 2 hours, followed by K〇H powder (31 g, 55.1 millimoles) . Stirring was continued for 6 hours at 15 (TC). The mixture was cooled to room temperature, poured into an ice/water mixture and extracted with diethyl ether. The combined extracts were dehydrated with MgSO 4 and concentrated in vacuo. Purification using hexane as a solvent to give y-bromo-3-(4,4,4-trifluoro-butyl)-benzene (2.4 g, yield 88%) as colorless oil. M) + 266; NMR (400 MHZ5 DMSO-d6) δ ppm, 1.7 - l.8 (m, 2 H), 2·1 - 2.2 (m, 2 H), 2.6 (t, /= 7.6 Hz, 2 H), 7.2 _ 7.25 (m, 2 H), 7·3 - 7.35 (m, 1 H), 7.4 (s, 1 H). Step d) 1-Difluoromethoxy-4-[3-( 4,4,4-Trifluorobutyl)phenylethynyl]benzene was used in essentially the same procedure as described in Example 1 Step a to give 1-difluoromethoxy-4-[3-(4, 4,4-Trifluorobutyl)phenylethynyl]benzene (19 g, 30% yield). m/e (M)+354; bNMR (400 MHZ, DMSO-d-6) δ ppm,1·74 - 1·78 (m, 2H), 2.17 - 2.21 (m, 2H), 2.62 - 266 (t , J = 7.65 Hz, 2H), 7.17 - 7.20 (d, J = 8·8 Hz, 2H), 7.23 - 7.39 (m, 5H), 7.56 - 7.58 (d, J = 8.8 Hz, 2H ). Step e) 1-(4-Difluoromethoxyphenyl)_2_[3-(4,4,4-trifluorobutyl)phenyl]ethane-1,2-dione as MgS〇4 (1.83 Gram, 15.25 millimoles) to treat acetone containing difluorofluoro-methoxy-[3-(4,4,4-trifluorobutyl)phenylethynyl]-benzene (7 62 mmol) 114619.doc -63- 200808735, followed by treatment with NaHC 3 (0.38 g, 4.57 mmol) of aqueous h20 and EtOAc (2. 41 g, 15.24 m.). The suspension was stirred for 2 hrs, diluted with hydrazine and diethyl ether and passed through a pad of cellulose powder. The filtrate was extracted with diethyl ether. The extract was washed with brine, dehydrated with EtOAc and concentrated in vacuo to give 1-(4-difluoromethoxyphenyl)[3-(4,4,4-trifluorobutyl)phenyl] Alkane-1,2-diindole. m/e (MH)- 385; 4 NMR (400 MHZ, CDC13) δ ppm,1·8 - 1·9 (m, 2 Η), 2·0 _ 2.1 (m, 2 H), 2.7 (t, J=7.8 Hz, 2 H), 6.6 (t5 J=72.6 Hz, 1 H), 7.2 - 7.2 (m5 2 H)? 7.4 - 7.5 (m, 2 H), 7.7 - 7.8 (m5 2 H), 8.0 - 8.0 (m, 2 H). Step f) 2-Amino-5_[4-(difluoromethoxy)phenyl]_3_methyl_5-[3-(4,4,4-di-butyl)phenyl]-3,5 - Di-argon-4H-Miso - The title product was obtained as a white solid, mp 7 (rc; m/e (Μ Η) 44 〇1; NMR NMR (400 ΜΗΖ, DMSO-d6) δ ppm, 1.64 - 1.68 (dd, /= 7.9 Ηζ, 2Η), 2·16 - 219 (m, 2Η), 2·54 '2·58 (t,7·76 Ηζ,2Η), 2.93 (s5 3Η)? 6.61 (bs5 2Η), 6.93 + 7.3 (s, lH), 7.04 - 7.06 (d5 7·6 Ηζ, 1Η), 7.23 (m, J = 8.81 Hz, 2Η), 7.18 - 7.19 (t? J = 3Η), 7·40 - 7·42 (d, 8.81 Ηζ, 2Η) ο Example 14 s-(3-{2-Amino winter (IV) industrial fluorine Preparation of methoxy)phenyl]small methyl_5_oxo_4,s·dihydro-1Η-imidazole-4_yl}phenyl)valeronitrile 114619.doc -64- 200808735

Step a) 4-(3-Bromophenyl)-4-oxo-butyronitrile The DMF mixture containing sodium cyanide powder (1.23 g, 25 mmol) was slowly treated with 3-bromo-benzaldehyde-containing DMF. After stirring at 35 ° C for 3 hours, cooled to room temperature, poured into a cooled 0.5N HCl solution and extracted with diethyl ether. The combined extracts were washed with aq. EtOAc EtOAc. The residue obtained was taken up in diethyl ether and filtered. The filter cake was dried to give 4-(3-bromophenyl)-4-oxo-butyronitrile as a yellow solid (4 g, yield: 58%), m/e (M) + 237; lU NMR (400 MHZ, DMSO-d6) δ ppm5 2.7 (t, J=6.7 Hz, 2 H), 3.5 (t, J = 6.7 Hz, 2 H), 7.5 (t, J = 7.8 Hz, 1 H), 7·9 (ddd , J = 7.9, 2.1, 0.9 Hz, 1 H), 8.0 (ddd, "7 = 7.8, 1.7, 0.9 Hz, 1 H), 8.1 (t, J = 1.7 Hz, 1 H). 114619.doc -65- 200808735 Step b) 4-(3-Bromophenyl)butanoic acid The title compound was obtained in the same manner as that described in the step (3). 93%). m/e (MH)- 241; 4 NMR (400 MHZ? DMSO-d6) δ ppm, 1.7-1.8 (m5 2 H)? 2.2 (t, /=7.4 Hz5 2 H)5 2.6 (t5 J=7.9 Hz , 2 H), 7.2 - 7.2 (m5 1 H), 7.3 (t, /=7.5 Hz, 1 H), 7.4 - 7·4 (m5 1 H), 7_4 - 7.4, (m5 1 H), 12.1 ( S5 1 H). Step c) 4-(3-Bromophenyl)butanol: THF was slowly treated with a solution of 4-(3-bromophenyl)butanoic acid (2.85 g '11.7 mmol) in m^THF (35 mL). Cool (〇.〇 solution, stir at room temperature for 18 hours, pour into ice/water, basify to pH=ll with 2 5 n NaOH and extract. Combine the extract, wash with brine, dehydrate with MgS〇4 and The residue was purified by column chromatography using hexane/CH.sub.2Cl.sub.2/MeOH (4/4.5/0.5) as solvent to afford 4-(3-bromophenyl)butan-1-ol as colorless oil. 1.9 g, yield 70%) m/e (M) + 228; lK NMR (400 MHZ5 DMSO-d6) δ ppm, 1.3 - 1.4 (m, 2 H) 1.5 _ 1.6 (m, 2 H), 2.55 _ 2·59 (m, 2 H), 3.3 _ 3.38 (m, 2H), 4·3 (t, J=7.5, 1H), 7.2 - 7.2 (m, 1 H), 7.3 (t, /= 7.5 Hz, 1 H), 7.4 - 7.4 (m, 1 H), 7.4 _ 7.4 (m, 1 H). Step d) Toluene-4·sulfonic acid 4-(3-bromo-phenyl)butyl ester as triethyl The amine (1.8 ml, 12.3 mmol) was slowly treated with 4-(3-bromophenyl)butan-1-ol (1.08 g, 4.7 mmol) and p-toluenesulfonyl chloride (1.2 g, 6.3 m) Mohr) THF cooling (〇°〇 solution, in the room After stirring for 4 hours, it was poured into ice-cooled saturated aqueous solution of ΝΗαΐ and extracted with diethyl ether. The organic extracts were combined with 114619.doc-66-200808735, and the mixture was washed with brine, dried with MgSO 4 and concentrated in vacuo. Purification using (hexane/EtOAc 9.5/0.5) as a solvent to afford 4-(3-bromophenyl)-butyl ester of toluene-4-sulfonic acid as colorless oil (2.4 g, yield 76%). /e (M+NH4)+ 400.1; 4 NMR (400 MHZ, DMSO-d6) δ ppm,1·4 - 1·6 (m,4 Η), 2·4 (s,3 H),2.4 - 2 · 5 (m, 2 H), 4.0 (t, J = 6.0 Hz, 2 H), 7.2 (t, J = 7.8 Hz, 1 H), 7.3 - 7·3 (m, 1 H), 7.3 - 7.3 (m, &gt; 8.0, 1·0 Hz, 1 H), 7·4 _ 7.5 (m, /=8.6 Hz, 2 H), 7.7 - 7.8 (m, 2 H) 〇Step e) 5-(3 _Bromophenyl)pentanonitrile 4-(3-bromophenyl)butylate containing toluene-4-sulfonate (2.3 g, 6 mmol) and powdered sodium cyanide (0.65 g, 13 mmol) The DMSO mixture of the ears was heated to 80 ° C, stirred for 1.5 hours and monitored by NMR. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with Ηβ and extracted with CH2C12. The combined organic extracts were washed with brine, dried with EtOAc EtOAc The residue was purified using EtOAc (EtOAc/EtOAc (EtOAc) . m/e (M)+ 237; 4 NMR (400 MHZ, DMSO-d6) δ ppm, 2·63 - 2·65 (m, 2Η), 2.75 - 2·78 (m, 2Η), 2·35 - 2·38 (m, 2Η), 2.60 - 2·63 (m, 2Η), 7.05-7.10 (m, 2Η), 7·25 - 7·28 (m, 2Η). Step f) 5-[3-(4-Difluoromethoxyphenylethynyl)phenyl]pentanenitrile was used in essentially the same procedure as described in Example 1 Step a; 4-Difluoromethoxyphenylethynyl)phenyl]pentanenitrile (54 g, yield 88%). m/e (M+H)+ 326; 4 NMR (400 MHZ, DMSO-d6) δ ppm,1·5 - 1·6 (m, 2 Η), 1.6 _ 1·7 (m, 2 Η), 2·5 (t, J=7.0 Ηζ, 2 114619.doc -67- 200808735 Η), 2.6 (t, J-7.5 Hz, 2 H), 7.3 (dd, J=?3 7 u 义 7 Hz, 1 H), 7.2 7.3 (m, 2 H), 7.3 (t, &gt; 7.4 Hz, 1 H) 7 4 Ί Λ (m, 1 H) 〇), 7.4 - 7.4 K i H), 7.4 7.4 Step g) Valentonitrile 5-{3-[2-(4-difluoromethoxyphenyl)_2-carbo-ethenyl]phenyl} was obtained using essentially the same procedure as described in Example 6 Step 6 to afford pale yellow oil. 5-{3_[2-(4_mylphenyl)_2_oxo_ethyl] quinone nitrile (0.46 g, yield 77%). m/e(M+H)+ 358; 1hnmr(4〇〇mhz, CDCI3) δ 1.20 ppm, 1.6 - 1.8 (m, 2 H), 1.7 - 2.0 (m, 2 H), 2 3 -2.5 (m , /=7.〇, 7.0 Hz, 2 H), 2.6 _ 2.9 (m, slice 5, 7 5 Hz, 2 H), 6 6 (t, /=72.7 Hz, 1 H), 7.2 - 7.4 (m , 2 H) 7.4 - 7.6, (m, 2 H) 7.6 - 7.9 (m, 2 H), 7.9 - 8.2 (m, 2 H). Step h) 5-(3-{2-Amino-4-[4-(difluoromethoxy)phenyl)methyloxo-4,5-dihydro-1H-imidazol-4-yl} Phenyl)pentanonitrile The title product was obtained as a white solid, mp. (:; m/e (M+H) 413 H NMR (400 MHZ, DMSO_d6) δ ppm, 1.4 _ 1.6 (m, 4 Η), 2·4 _ 2.5 (m, 2 Η), 2.5 (t, J =7.2 Ηζ, 2 Η), 2.9 (s, 3 Η), 6.6 (bs·, 2 Η), 7·1 (t, /=74.2 Ηζ, 1 Η), 7.0 _ 7·1 (m, 3 Η ), 7.2 (t, J=7.8 Ηζ, 1 Η), 7·2 · 7·2 (m, 2 Η), 7·4 _ 7·5 (m, 2 Η). Example 15 4-(3- (2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5.oxo-4,5-dihydro-1Η-imidazol-4-yl}phenyl) Butyronitrile 114619.doc -68- 200808735

Using essentially the same procedure as described in Example 14 and using 3-(3-bromophenyl)propanoic acid, the title product was obtained as white solid, 0.23 g (yield 48%), mp 75 〇 C; m/e (M +H)+ 399; lU NMR (400 MHZ, DMSO-d6) δ ppm5 1.73 - 1.76 (m5 2 H)? 2.44 - 2.46 (m5 2 H)? 2.55 - 2.59 (t5 J=7.8 Hz, 2 H), 2·9 (s,3 H),6.6 (bs·,2 H),7·05 - 7.07 (d,J = 8.7 Hz? 2 H), 7.13 - 7.32 (m5 5 H), 7.41 - 7.43 (d ? J = 8.7 Hz5 2 H). Example 16 2-Amino-5-[3-(l,4-difluorobutyl)phenyl]-5-[4-(difluoromethoxy)phenyl]- 3-indolyl-3,5 ·Preparation of dihydro·4Η-imidazol-4-one

Cul, dioxane, 40°c 114619.doc -69- 200808735

Step a) 4-(3_Bromophenyl)but-3-yne-1-fermented 1 〇·0 g (35·3 mmol) 3_A-Bromobenzene DMF solution at 2.95 ml (88 耄) Molar) 4·butyn-1-ol, 0.2 g (1.00 mmol) copper iodide (1), h23 g dichlorobis(triphenylphosphine)_palladium (11) and 49 ml (〇·35 Mol) triethylamine treatment 'stirred at room temperature for 18 h, poured into water and extracted with EtOAc. The combined extracts were washed successively with water and brine, dehydrated with NaJO4 and concentrated under reduced pressure. The resulting concentrate was subjected to 5% to 30% EtOAc-hexanes gradient chromatography eluting EtOAc EtOAc EtOAc Yield 92%); NMR (4 〇〇 MHz, CDCl3) δ: i 79 (s, 1H), 2 67 (t, 2H, J = 6.3 Hz), 3.80 (t, 2H, J = 6·3 Hz ), 7.14 (t, 1H, / = 7.9 Hz), 7.30 (d, 1H, 7·9 Hz), 7·41 (m, 1H), 7.54 (t, 1H, 1.6)

Hz) 〇Step b) 1-Bromo-3-(4-fluoro-but-1-ynyl)benzene treated with 2.0 ml (15.3 mmol) of DAST at 〇C containing 1.5 g (6.67 mmol) A solution of 4-(3-bromophenyl)but-3-yn-1-ol in CH2C12 was scrambled at 0 ° C for 1 h, allowed to warm to room temperature for 1 h, and poured into saturated sodium bicarbonate solution. It was extracted with EtOAc. The combined extracts were washed with water and brine, dried over Naz. The resulting concentrate was subjected to a gradient of 〇% to 24% EtOAc-hexanes on silica gel to give a volatile liquid of &lt;RTI ID=0.0&gt; Yield 64%); 4 NMR (400 114619.doc -70-200808735 MHz, CDC13) δ: 2.82 (dt5 2H, /= 6.6, 19·8 Hz), 4.56 (dt, 2H, J = 6.6, 46.4 Hz ), 7·14 (t, 2H, 7.9 Hz), 7.31 (m, 1H), 7.41 (m, 1H), 7.55 (t, 1H, / = 1.7 Hz). Step c) 1-(3-Bromophenyl)-4-fluorobutan-1-one will be 0.22 g (0·89 mmoles of fluorobuty-indole-alkynyl)benzene, 2 ml of MeOH, 1 mg of A A mixture of (triphenylphosphine) gold (1), 25 microliters of concentrated 8 〇 4 and 0. 44 ml of HA was placed in a sealed tube, rinsed with argon, heated to 72 ° C for 2 h and cooled. The reaction mixture was diluted with EtOAc (EtOAc m.). The concentrate was chromatographed on a gradient of 0/) to 20% EtOAc-hexanes to afford the oily ι_(3_bromophenyl)-4-fluorobutan-1-one, 〇 〇 86 g ( Yield 40%); 4 NMR (400 MHz? CDCI3) δ: 2.13 (m, 2H), 3.09 (t5 2H, J = 7.1 Hz), 4.53 (dt, 2H, / = 5.8, 47.1 Hz), 7.33 ( t,1H,7.8 Hz), 7.66 (dq, 1H, J= 1.0, 7.8 Hz), 7.55 (dq5 1H3 J= 1.0, 7.8 Hz), 8.07 (t, 1H, /= 1.7 Hz) 〇Step d) 1 -Bromo-3-(l,4-difluoro-butyl)benzene treated with 0.055 g (1.47 mmol) solid state sjaBH4 at 〇C containing 〇·3 g (1·22 house Moer) 1-( 3-thyl phenyl)-4-fluorobutan-1-one thf solution, in hydrazine. The mixture was stirred for 0.5 h, warmed to EtOAc EtOAc. Separate the phases. The organic phase was washed with water and brine, and then dried over Na[sub][sub][sub][sub][sub][sub][sub][sub][[[[[[[[ %) oil. The oil was dissolved in CHAh, cooled to (TC, treated with 毫升 23 ml (1·75 mmol), stirred at 0 ° C for 5 h, allowed to warm to room temperature, and The mixture was stirred at room temperature for 14 h, and the mixture was stirred with EtOAc (EtOAc). For further purification, use in step e. Step e) (Difluoromethoxy)phenyl]ethynyl}phenyl)-1,4-difluorobutanin containing 13 mg (0.034 mmol) of double ( To the debenzylation solution of benzonitrile) dichloro-dioxane, 0.145 g (0.072 mmol) of 1 Torr was added. /〇(^^/~) Three-third butylphosphine hexane. The reaction mixture was stirred at room temperature for 5 minutes, treated with 4.33⁄4 g of copper (I), then treated with 2 2 ml of diisopropylamine, stirred for 10 minutes to dissolve in 2 ml of dioxane. 0.28 g (1.14 mmol) of 1-bromo-3-(1,4-difluoro-butyl)benzene and hydrazine. 25 g (1.48 mmoles of difluoromethoxy-4-ethynyl-benzene) The reaction mixture was heated to 35 ° C. for 5 h, allowed to cool to room temperature, stirred at room temperature for 3 h, poured into Et0Ac. The organic phase was separated and washed sequentially with water and brine to Na2s The hydrazine was dehydrated and concentrated under reduced pressure. The concentrate was chromatographed on silica gel eluted with 〇% to 25% EtOAc (hexane) to afford 1-(3-{[4-(difluoromethoxy)benzene. Acetylene}phenyl)-1,4-difluorobutane, 〇·3ΐ4 g (yield 82%); A NMR (400 MHz, CDC13) δ: 1.77-2.07 (m, 4H), 4.51 ( m, 2H), 5.48 (dq, 1H5 J = 4.4, 47.6 Hz), 6.51 (t, 1H, 73.5 Hz), 7.08 (d, 1H, 8.6 Hz), 7.22-7.36 (m, 3H), 7.45-7.52 (m, 3H). Step f) 2_Amino_5-[3_(1,4-difluorobutyl)phenyl b 5 [heart (difluoromethoxy)phenyl]_3_methyl_ 3,5-two -4H-imidazol-4-one was used in substantially the same procedure as described in Example 13, Step e, and Example 1, Step c, and using 1-(3-{[4-(difluoromethoxy)phenyl]ethynyl}benzene Base)_i,4_114619.doc -72- 200808735 Difluorobutane was used as the starting material to obtain a foamy solid title product 'mP 54-57 °C; lU NMR (400 MHz, DMSOd6) δ: 1.61-1.91 ( M5 4H)? 2.94 (s,3H),4.34-4.50 (m,2H),5.43-5.58 (m,1H),6.67 (br s,2H), 7.06 (d5 2H5 J- 8.8 Hz)5 7.12 (t5 1H5 J = 74.2 Hz) 5 7.2 (d5 1H, 7.4 Hz), 7.28 (d, 1H, /= 7.7 Hz), 7.40 (m, 4H). MS (ESI) m/z 424.2 ([M+H])+ & MS (ESI) m/z 422.2 ([M-H]). Example 17 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluorobut-3-yl-1-yl)phenyl]-3-indenyl- Preparation of 3,5-dihydro-4H-imidazolone

d Step a) 1-Bromo-3-but-3-enylbenzene was treated dropwise with 2.3 ml of 1. 6 M n-BuLi in hexane (3.77 mmol) containing 1.34 g (3.77). Milliol) decyltriphenylscale bromo THF solution, stirred at 〇 ° C for 0.25 h, cooled to -78 ° C, containing 3-(3-bromophenyl)propanal (0.7 g ' 3 · The 28 mM solution of THF was treated dropwise, and the mixture was stirred for 1 h, and allowed to warm to room temperature. The reaction was quenched with ΝΗβΙ aqueous solution and concentrated under reduced pressure 114619.doc -73 - 200808735. The residue was taken up in EtOAc EtOAc EtOAc. The concentrate was chromatographed on EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Yield 〇%); 咕 (like MHz, CDC13) δ: 2.33 (m, 2H), 2.66 (t, 2H, / = 7.4 Hz), 4.98 (m, 2H), 5·79 (m, 1H) , 7.12 (m, 2H), 7.30 (m, 2H). Step b) 1-bromo-3-(3-fluoro.4-moth-butyl)-benzene at 〇C containing 0. 39 g (1.74 mmol) of N-iodosuccinimide and 1〇5克(1.743⁄4摩尔) 50% wt/wt tetrabutylammonium dihydrotrifluoride CH2Cl2 treatment containing 0.245 g (1.16 mmol) of 1-bromo-3-but-3-enylbenzene The solution was stirred at 0 ° C for 2 h, warmed to room temperature over 1 h, and poured into CH 2 Cl 2 . The obtained organic phase was washed with water and brine, dried over Na 2 S 〇 4 and decompressed. The liquid was subjected to gradient chromatography on EtOAc-hexanes to give oily 1-bromo-3-(3-fluoro-4-c-butyl)-benzene, 〇·40.克(yield 50%); towel NMR (400 MHz, CDC13) δ: 2.03 (m, 2Η), 2·74 (m, 2H), 3.29 (dd, 2H, "/= 5.4, 19.1 Hz), 4 · 47 (m, 1H), 7.12 (m, 2H), 7.32 (m, 2H). Step c) 1-bromo-3-(3-fluorobut-3-enyl)benzene at room temperature with 0· 82 ml (5·5 mmol) of DBU was treated with 0.405 g (1.1 mmol) of 1-bromo-3-(3-fluoro-4-iodobutyl)-benzene in CH2C12 and stirred at room temperature. h, and poured into EtOAc. The obtained organic phase was washed with water and brine, and dried over NaH.sub. Fluorin-3-yl alkenylbenzene, 0.20 g (yield 80%); 4 NMR (400 MHz, 114619.doc -74 - 200808735 (dd, 1H, (m, 2H), CDCl3) δ: 2.45 (m, 2H), 2.78 (t, 2H, 7, 8 Hz), 3 29 /= 2.8, 5 〇.1HZ), 4.5 〇 (dd, lH, J = 2.8, 7.3 Hz) '7. 7·32 (m, 2H). ' -3-dilution step d) 2 · Amine j [4 fluorofluoromethoxy) phenyl b 5 you (3_fluoro 1-yl) stupid]-3-methyl _3,5_ two gas _ 411-Miso_4__ Using the same shoe sequence as described in Example 1, steps a, ..., and using 1 M3-fluorobutanyl)benzene as a starting material, a yellow-brown foamy solid title was obtained. Product, mp 58-6 (rc; 1H NMR (4(9) MHz, DMSOd6) δ: 2.39 (m5 2H), 2.64 (m5 2H)? 2.93 (s, 3H)5 4.29 (dd, 1H, J = 8.8, 52·0 Hz), 4.47 (dd, 1H, / = 2.9, 18.2 Hz), 7.05 (brs, 2H), 7·12 (t, 1H, J = 74.2 Hz), 7.08 (m, 3H), 7·15 (m) , 1H), 7.25 (m, 1H), 7.40 (m, 2H), 7.54 (m, 1H); MS (ESI) m/z 404.1 ([M+H])+ and MS (ESI) m/z 402.1 ([MH])-. Example 18 2-Amino-5-[3-(4,4-difluorobut-3-en-1-yl)phenyl]-5-[4-(difluoromethoxy) Preparation of phenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one

114619.doc -75- 200808735 Step a) 3-[3-(4-Difluorodecyloxyphenylethynyl)phenyl]propene was used essentially in the same procedure as described in Example 16, step e and used % (3_Bromophenyl)propanal in place of 1-bromo-3-(1,4-difluoro-butyl)benzene to give oily 3-[3-(4-difluoromethoxyphenylethyl) benzene Base] Awakening: The yield was 42%. This was used in the next step without further purification. Step b) 1-(3-{[4-(difluorodecyloxy)phenyl]ethynyl}phenyl)-4,4-dioxane-3-thin at -78 ° C at 0·54 ML (0.54 mmol) 1_6 M n_BuLi hexane solution containing 0.122 ml (〇·86 mmol) of diisopropylamine in THF, wrestling at -78 C for 5 h, containing 0-22 g ( 0.86 millimolar) dimethyl diphenyltriphenylphosphine oxide in THF solution was treated dropwise, stirred at -78 ° C for 45 minutes to contain 0.17 g (0.58 houser) 3-[3-(4- two Treatment with THF solution of fluoromethoxyphenylethynyl)phenyl]propanal, stirring at -78 °C for 4 h, warming to room temperature ' stirring at room temperature for 18 h and diluted with CEbCh. The organic phase was washed successively with water and brine, dried over Na 2 EtOAc and evaporated. The concentrate was subjected to gradient chromatography on a silica gel to 10% EtoAc-hexane to obtain an oily compound (3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)_4. 4, difluorobutene, 0.09 g (yield 52%); 4 NMR (400 MHz, CDC13) δ: 2·29 (m, 2 Η), 2.66 (t, 2 Η, / = 7·6 Ηζ), 4·13 (m5 1Η), 6.50 (t, 1Η, J= 73.6 Hz), 7.07 (d, 2H, /= 8·8 Hz), 7.13 (m, 1H), 7·26 (d, 1H, / = 8.8 Hz), 7.34 (m, 2H), 7.49 (dt, 2H, /= 2.1, 2.6, 8·3 Hz). Step 〇) 2-Amino-5_[3-(4,4-difluorobut-3-en-1-yl)phenyl]-5-[4-(difluoromethoxy)phenyl]-3 Mercapto-3,5-di-argon-4H-imidazolone was used essentially as in the procedure described in Example 1, steps b and c and used 1 _ 114619.doc -76- 200808735 (3-{[4-(difluoro) Methoxy)phenyl]ethynyl}phenyl)-4,4-difluorobut-3-ene as the starting compound gave the title compound as a pale yellow solid, mp 59-62 ° C; 4 NMR (400 MHz, DMSOd6) δ: 2.14 (q? 2H5 J = 7.4 Hz) 5 2.49 (m, 2H), 2.93 (s, 3H), 4.37 (m, 1H), 6.60 (brs, 2H), 7·05 (d, 2H3 J= 8.7 Hz)5 7.12 (t5 1H, J= 74.2 Hz) 5 7.18 (m? 2H)? 7.21 (m, 2H), 7.40 (d, 2H, / = 8.7 Hz); MS (ESI) m/z 422.1 ([M+H])+ and MS (ESI) m/z 420.1 ([M-Η])·. Example 19 2-Amino-5-[3-(4,4-difluorobutyl)phenyl b-[4-(difluoromethoxy)phenyl]·3·methyldiazepine_4H- Preparation of imidazole-4-one

Step a) 1-Bromo-3-(4,4-difluorobutyl)benzene is treated with a solution of diethylamine trifluoride (DAST) (0.38 mL, 2.8 mmol) in a solution of hexane. (3-Bromophenyl) Dinglu (〇·6 g, 2.6 mmol) of pentoxide solution was stirred at room temperature for 1 h, poured into water and extracted with acetonitrile. The extract was combined, washed with brine, dried over magnesium The residue obtained was purified by flash chromatography on hexane to give a transparent oily material: 114619.doc-77-200808735 bromo-3·(4,4-difluorobutyl)-benzene, 〇·36 g 4 NMR (DMSO-d6) δ 1.7 (m5 4H); 2.6 (t5 2H); 6.6 (txd5 1 H); 7.2 (m5 2H); 7.38 (d, 1H), 7.39 (s, 1H) ). Mass Spectrum [(+)ESI] m/z = 248 [M_H]+. Step b) 2-Amino-5_[3-(4,4-difluorobut-3-ene-1-yl)phenyl b-5[4-(difluoromethoxy)phenyl]-3- Methyl-3,5-dihydro-4H-imidazol-4-one was used essentially the same procedure as described in Steps a and c of Example 18 and using 1-bromo-3-(4,4-difluorobutyl) - Benzene and 1-difluoromethoxy-4-ethynylbenzene as the reactants gave the title compound as a white solid, 0.17 g (yield 42%), mp 54-57 〇C; lU NMR (DMSO-d6) δ 1.6 (m5 2H); 1.8 (m5 2H); 2.5 (t, 2 H); 2.95 (s, 3H); 6.0 (txd, 1H); 6.6 (b, 2H); 7.1 (m, 4H); · 4 (d, 2H). MS [(+)ESI] m/z 424 [M-H]+. Example 20 2-Amino-5-[4-(difluorodecyloxy)phenyl]-5-[3-(4-polybutyr-1-yl-1-yl)phenyl]_3_methyl Preparation of _3,5-diaza-4H- miso _4-嗣

In the gas, magnetized copper (8 mg, 〇·〇 4 mmol), bis(nickel) nitrile (11) (233⁄4 g '0.063⁄4 mol) and anhydrous two were used. The mixture of smoldering was stirred for 3 minutes, treated with di-second butyl phosphine (10% in hexane) (240 mg, 0.12 mmol), stirred for 5 minutes with diisopropylamine (33 ml) , 2. 4 millimolar), followed by 2-amino--5-(3-bromophenyl)_5_[4_(difluoromethoxy 114619.doc-78-200808735)phenyl]-3- Treatment of methyl-3,5-dihydro-4H-imidazole-4-one (0.82 g, 2 mmol) in dioxane and 1-hydroxy-2-propyne (0.47 mL, 0.006 mmol) . The reaction mixture was heated to 35 &lt;0&gt;C for 30 min, poured into water and extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate The residue was purified by flash chromatography on EtOAc EtOAc EtOAc (EtOAc) , mp 90-93 ° C; 4 NMR (DMSO-d6) δ 2·5 (2H, under DMSO peak); 2.95 (s, 3 H); 3.5 (q, 2 H); 4.8 (t, 1 H) ; 6.6 (b, 2H); 7.1 (d, 2H); 7.15 (t, 2F); 7.2 (m, 2 H); 7.3 (m, 4 H); MS [(+)ESI] m/z = 400.2 Example 21 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybutyl)phenyl]-3-methyl-3,5-dihydro Preparation of -4H-imidazol-4-one

Will contain 2-amino-5-[4-(difluorodecyloxy)phenyl]-5.[3-(4-hydroxybut-1· 快·1 _)phenyl]-3 _methyl -3,5 - 二气_4Η·^ σ sit-4-class (0.26 g, 0.65 mmol) ethanol solution and 5% palladium/carbon (26 mg) mixture in a 40 psi hydrogen paar hydrogenator In 8 h. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut elut elut elut ) δ 1.4 114619.doc • 79- 200808735 ((2H, 2H); 1·5 (m, 1 H); 2.5 (2H, under DMSO peak) 2.95 (s, 3 H); 3.3 (q, 2 H) ; 4.3 (t,1 H); 6·6 (b,2H); 7·1 (m,3H); 7.15 (t, 2F); 7.2 (m5 3 H); 7.4 (d? 2 H); MS [(+)ESI] m/z = 404 [MH]+. Example 22 2-Amino-5-[4-(difluorodecyloxy)phenyl b-5-[3_(3-methoxypropane- 1-yne-1_yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one

Treatment of 1-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]_3 with 3-methoxypropyne (0.27 mL, 3.2 mmol) _Methyl_3,5-dihydro-4H_imidazol-4-one (0·65 g, 1.6 mmol) pyrrolidine solution followed by hydrazine (triphenylphosphine) palladium (0) (90 Treatment in milligrams (0. 08 mmol), heated to 8 ° C for 4 h, poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate Remnant

The title compound, 0.4 g (yield: 63%), was confirmed by NMR and mass spectrum analysis. Example 23 2-Amino-5-[4-(difluoromethoxy)phenyl ρ5-{3-[(1ζ)_3_methoxypropen-1-yl]phenyl}_3_methyl-3 Preparation of 5-dihydro-4Η-imidazole 114619.doc -80- 200808735

Will contain 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3_(3-methoxyprop-1-n-l-yl)phenyl]_3_methyl -3,5-dihydro-4H_imidazol-4-one (〇·1 g, 〇·25 mmol) in ethanol (1.5 ml), quinoline (1 drop) and Lindlar catalyst (24 mg, The mixture of 1 mol% of the mixture was placed in a state of filling with a hydrogen balloon, stirred for 16 h and filtered through diatomaceous earth. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut elut elut δ 2.95 (s5 3H); 3.2 (s, 3H); 4.0 (d, 2H); 5.7 (q, 1H) 6.5 (d, 1H); 6.6 (b, 2H); 7.1 (m, 3H); m, 4H); 7.4 (d5 2H); MS [(+)ESI] m/z = 402 [MH]+. Example 24 2-Amino-5-[4-(difluoromethoxy)phenyl b-[3-(3-methoxypropyl)phenyl-methyl-3,5-dihydro-4Η-imidazole Preparation of _4·ketone

Will contain 2-amino-5-[4-(difluoromethoxy)phenyl]_5_[3_(3-methoxyprop-1-en-1-yl)phenyl]-3-methyl_ A mixture of 3,5-dihydro-4-indole-imidazole-4-one (0.1 g, 0.25 mmol) in ethanol and 1% palladium on carbon (1 mg) was placed at 114619.doc -81 - 200808735 In the state of a hydrogen balloon, it was stirred for 16 h and filtered through diatomaceous earth. The filtrate was concentrated to dryness in vacuo. The residue was purified by flash chromatography on silica gel eluting eluting elut elut elut elut elut elut elut elut elut elut δ 2.4 (m5 2H); 2.95 (s, 3H); 3·2 (s, 3H); 3·3 (t, 2H); 6.6 (b, 2H); 7.1 (m, 3H); 7.2 (m , 4H); 7.4 (d, 2H); MS [(+)ESI] m/z = 404 [MH]+. Example 25 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentyl)phenyl-3-methyldihydro-4H-imidazole_4_ Preparation of ketone

Step a) 5-(3-Bromophenyl)pentan-1-enzyme containing 5-(3-bromo-phenyl)-pent-4-enol (40, psi) (Example 3, step a) A mixture of ethanol solution and platinum oxide (24 mg, mol%) was placed in a Parr shaker for 4 h. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue obtained was purified by flash chromatography on a silica gel for 10 min using 10:1 hexane/ethyl acetate for a second time and 2:1 hexane/ethyl acetate as 114619.doc-82-200808735. 5_(3_Bromophenyl)pentapropanol, 0.75 g (yield 74%); NMR (DMSO-d6) δ 1.2 (m, 2H); 1·3 (m, 2H); m,2 H); 3·3 (q,2H); 4.3 (t,1 H); 7·2 (m,2 H); 7.4 (m,2 H) MS [(+)ESI] m/z = 243 [MH]+. Step b) 1-brook_3-(5-fluoropentyl)benzene at -78 ° C with diethylaminosulfur trifluoride (DAst) ((K7 ml, 5 · 2 mmol) The methylene chloride solution was treated with a solution of 5-(3-bromophenyl)pentan-ol-ol (0.63 g, 2.6 mmol) in dichloromethane, which was allowed to warm to room temperature and stirred at room temperature for 5 h. The mixture was poured into water and extracted with diethyl ether. The combined extracts were washed sequentially with saturated sodium hydrogen carbonate and water, dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography to obtain 1-bromo-3-(5-fluoropentyl)benzene as a pale yellow oil, y. 4 g (yield: 63%), lU NMR (DMSO «d6) δ 1.3 (m5 2H ); 1.6 (m, 4H); 2.5 (t, 2 H); 4.4 (dxt, 2H); 7.2 (m, 2 H); 7·4 (m, 2 H); MS [(+)ESI] m /z = 245 [MH] X. Step C) 2-Amino-5-[4-(difluoromethoxy)phenyl]_s_[3(5fluoropentyl)phenyl]-3-methyl- 3,5-Dihydro-4H-miso-4-indole was used essentially in the same procedure as described in Example 18, Steps a &amp; c, and using dimethyl-3-(5-pentyl)benzene and hydrazine. Methoxyethynylbenzene as a reactant' to obtain a white solid Compound ο·04g (yield 18%); 1hnmr (DMSO-d6) δ 1.3 (m, 2H); 1.6 (m, 4H); 2.6 (t, 2 H); 2.95 (s, 3H); 4.4 (dxt, 2H); 6.6 (b, 2H); 7.0 (m, 3H); 7 2 (m, 4H); 7 4' (d, 2H); MS [(+)ESI] m/z 420 [ MH]+ 〇Example 26 114619.doc •83· 200808735 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3_(4·fluorobutyl)phenyl b-3-A Preparation of _3,5·dihydroimidazole-4 ketone

Using the same procedure as described in Example 25 and using 1-bromo-3-(4-butylbutyl)benzene to give the title compound as a white solid; iHNMR (DMSO-d6) δ 1.6 (m, 4H); m, 2 H); 2.95 (s, 3H); 4.4 (dxt5 2H); 6.6 (b, 2H); 7.0 (m5 3H); 7.2 (m, 4H); 7.4 (d, 2H); MS [(+ ESI] m/z = 406 [MH] + 〇 Example 27 2Amino 5-[4-(monofluoromethoxy)phenyl b-5-[3_(6-f-hexyl)phenyl b-3-methyl_ Preparation of 3,5·dihydromyristone

The white solid title compound was obtained using essentially the same procedure as described in Example 25 and using benzene to give a white solid title compound, 1HNMR_SO-d6 δ U (m, 4H); 1 &gt; 6 (m, 4H); , 2 h); 2 % &amp;3h); heart (dxt, 2H); 6·6 (b, 2H); 7.0 On, 3HV 7 ^ MS [(1) 冈m/z 434 [M_H]+. ), 7.2 (called 4H); 7.4 (d, 2H) Example 28 114619.doc •84· 200808735 2-Amino-5-[4-(-fluoromethoxy)phenyl]ββ5·[3_(6_ Preparation of p-hexyl)phenyl]methanol methyl-3,5·dihydro-4Η·imidazolone

Step a) 1-light-3-(4-methoxybutyl)benzene to cool a mixture containing sodium hydride [60% in oil] (no mg, 3·3 mmol) and τΗρ to _5° C, treated with a solution of 4-(3-bromophenyl)butan-1-ol (0.7 g, 3.03⁄4 mol) in THF over 1 min, warmed to room temperature and stirred at room temperature. After 5 h, it was treated with decyl iodide (4·6 g, 35 mmol), stirred for 2 h, poured into saturated ammonium chloride and extracted with diethyl ether. The combined extracts were washed with brine, dried over magnesium sulfate The residue was purified by flash chromatography on silica gel eluting with 40:1 hexane/ethyl acetate as eluent to give 1-bromo-3-(4-methoxybutyl)benzene as a clear oil. (yield 51%); 'Η NMR (DMSO-d6) δ 1.4 (m? 2H); 1.5 (m5 2H); 2.5 (t5 2

H); 3.2 (s,3H); 3.3 (t,2H); 7.2 (m,2H); 7.4 (m,2H); MS

[(+)ESI] m/z = 244 [M-H]+. Step b) 2-Amino-5-[4-(difluorodecyloxy)phenyl]-5-[3-(4-methoxybutyl)phenyl]-3-methyl-3,5 _Dihydro-4H-imidazole·4-one 114619.doc -85 - 200808735

The procedure was used essentially as described in Example 18, Steps a &amp; c, and using Buqian-3-(4-methoxybutyl)benzene and 1-difluoromethoxy-4-methylhexylbenzene as reactants , mp · in NMR (DMSO-d6) δ 1·4 (m, 4H); 2.5 (m, 2 H); 2·95 (s5 3H); 3·2 (s, 3H) 3.3 (t, 2H); 6·6 (b, 2H); 7.0 (m, 3H); 7·2 (m, 4H); 7 4 (d, 2H); MS [(+)ESI] m/ z 418 [MH]+. Example 29 3-{2-Amino-4-[4-(difluoromethoxy)phenyl]_1-methyl-5-oxo-4,5-dihydro-1H-imidazole-4-yl Preparation of N-propylbenzylamine

1) t-Bu3P, (PhCN)2PdCl·Cul, diisopropylamine

Π2Ν Κ Step a) 3-Bromopropyl-benzylamine A mixture of dichloromethane containing N-propylamine (0.33 ml, 4.1 mmol) and triethylamine (〇·83 mL, 5.8 mmol) Cool to _5, treat with 3-bromobenzamide chloride (1 g, 4.5 mmol), warm to room temperature, stir at room temperature for 1 h. Pour into saturated sodium bicarbonate and dihydrate. Alkane extraction. The extracts were combined and washed with water and brine, dehydrated with sulphuric acid and purified by celite on 2:1 hexane/ethyl acetate as a solution to obtain white solid 114619.doc -86 - 200808735 State 3-bromo-N-propyl-benzylamine, 〇·74 g (yield 67%); 4 NMR (DMSO-d6) δ 0.8 (t, 3H); 1.5 (m, 2H); (t,2H); 7·4 (t,1H); 7.6 (d,1H),7.8 (d,1H); 7.9 (s,1H); 8·5 (b,1H); MS [(+) ESI] m/z 242[MH]+ 〇Step b) 3-{2_Amino-4-[4-(difluorodecyloxy)phenyldi-1-indolyl-5-oxo_ 4,5 _Dihydro-1H-imidazole_4_ kib N-propylbenzylamide using essentially the same procedure as described in Example 18, steps a and c, and using 3-bromo-N-propyl-benzylamine and hydrazine _ </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; (s? 3H); 3.2 (t, 2H); 6.7 (b, 2H); 7.1 (d, 2H); 7·3 (m, 1H); 7.4 (d, 2H); 7.5 (d, 1H); 7.6 (d, 1H), 7.7 (s, 1H); 8.4 (b, 1H); MS [(+)ESI] m/z 417 [MH]+. Example 30 2-Amino-5_[4-(difluoromethoxy)phenyl b-{3-[(2-fluoroethoxy)methyl]phenylmethyl-3,5-dihydro-4II -Preparation of imidazole-4-ketone

1) t-Bu3P, (PhCN)2PdCl2, Cul, diisopropylamine

Step a) Deodorant-3_(2-fluoroethoxymethyl)benzene was treated with sodium hydride in a solution containing 2-fluoroethanol in THF at _5 C. Containing sodium hydride 114619.doc -87- 200808735 [60% A mixture of oil (343 mg, 8.6 mmol) and THF lasted! In a minute, stir for 2 minutes, warm to room temperature, stir at room temperature for 15 minutes, treat with 3-bromobenzyl bromide (2.5 g, 11.7 mmol), stir 丨h, pour saturated chlorination Extracted in ammonium and with diethyl ether. The combined extracts were washed with water and brine, dried over magnesium sulfate and evaporated. The residue was purified by flash chromatography on 20:1 hexane/ethyl acetate as a solvent to obtain a yellow oil.

1-Bromo-3_(2-ethoxyindolyl)benzene, 1 g (yield 58%); 4 NMR (DMSO-d6) δ 3.6 (dxt, 2H); 4·5 (dxt, 2H); 4.4 (s, 2 H); 7.3 (m, 2H); 7.5 (m, 2H); MS [(+)ESI] m/z 219 [MH]+. Step b) 2-Amino-5_[4-(difluoromethoxy)phenyl]_5·{3-[(2-fluoroethoxy)methyl]phenyl}-3-methyl-3, 5-Dihydro-4 oxime-miso-4-one was used in essentially the same procedure as described in Example 18, steps a and c, and using bromo-3-(2-fluoroethoxymethyl)benzene and 1-difluoro Methoxy ethynyl benzene as a reaction gave the title compound as a white solid, mp 40-43:: 4 NMR (DMSO-d6) δ 2.95 (s5 3H); 3.6 (dxt, 2H); 4.4 (m3 3H); (t5 1H); 6.7 (b, 2H); 7.1 (d, 2H); 7.2 (m, 1H); 7·3 (m, 1H); 7.4 (m, 1H); 7.5 (m, 3H); [(+)ESI] m/z 408 [Μ·Η]+. Example 31-39 2-Amino-5·[4-(difluoromethoxy)phenyl]_5_[3-(alkoxymethyl)phenyl b 3_methyl_3,5·diar _4H - Preparation of oxime _4_ ketone l) t-Bu3P, (PhCN) 2PdCl2, Cul, diisopropylamine

114619.doc -88 - 200808735 The compounds shown in Table I were obtained using essentially the same procedure as described in Example 30 and using the desired alcohol in step a and determined by NMR and mass spectrometry.

Table I

Mp °C example [M+H]+

No. R 31 CH2CH2CF3 46-48 458 32 ch3 70-72 376 33 CH2CH2CH2CH3 37-39 418 34 ch2-&lt;] 47-50 416 35 CH2CH3 45-48 390 36 ch2ch2ch3 40-43 404 37 CH(CH2F)CH2F 46- 50 440 38 ch2cf3 50-52 441 39 ch2cf2chf2 48-50 476 Example 40 2-Amino-5-[4-(difluoromethoxy)phenyl]-5_{3-[(1Ε)-6-曱 Oxygen Preparation of hexyl-1-ene-1-yl]phenyl phenyl 3-mercapto-3,5-dihydro-4H-imidazol-4-one 114619.doc -89 - 200808735

Step a) (E)-6-methoxy·hex-i-dilute-acids thiol-containing hexyl ether (7.2 moles), THF containing o·5M9-BBN (1.8 ml) , 〇·9 mmol) and a mixture of tea phenol borane (121 g, 1 〇 1 mmol) heated in a pressure tube at 丨 (10) for 16 h, quenched with pH 7 phosphate buffer 'stirring 2 h, and extracted with diethyl ether. The combined extracts were dehydrated with MgSCU and concentrated in vacuo. The residue thus obtained was purified by flash chromatography to give (E)-6-methoxy-hex-i-alkenyl-p-acid, which was confirmed by nmr and mass spectrometry. CH-NMR 300 MHz, CDC13+D20): 6.52 (dt, 1H); 5.44 (dt, 1H); 3.40 (t5 2H); 3.35 (s5 3H); 2.21 (ddt3 2H); 1.68- 1.45 (m, 4H) ). Step 1&gt;) 2-Amino-5-[4-(difluoromethoxy)phenyl b-5-{3_[(11:)_6-methoxyhex-1-en-1-yl]phenyl }_3_Methyl-3,5-dihydro-4Ή-bee 嗤4-嗣 is treated with Pd(CH3CN)2Cl2 (20 mg, 5%) containing 2-amino-5·(3-bromophenyl) -5-[4-(Difluoromethoxy)phenyl]_3_methyl_3,5-dihydro-4Η-Miso-4-indole (200 mg, 0.488 mmol) and (E)_6 1 mM methoxy-hexan-; μ alkenyl-acid (0.537 mmol) in 1 ml of 2M K2C 〇3 and 2·5 ml 〇με degassing solution, the mixture was heated at 95 ° C and nitrogen for 16 h It was diluted with water and extracted with 114619.doc -90-200808735 CH2C12. The extracts were combined, dried over MgSO4 and evaporated. The residue obtained was purified on EtOAc EtOAc (EtOAc). CH-NMR 300 MHz, CDC13): 7.49 (d, 2H); 7.42 (s br, 1H); 7.27 (m, 5H); 7.06 (d5 2H); 6.49 (dd, 1H); 6·36 (d, 1H); 6·20 (dt,1H); 3·41 (t,2H); 3.35 (s,3H); 3.12 (s,3H); 2.22 (dt, 2Η);1·69-1·47 ( m, 4H) 〇MS [M+H]+ 444.4. Example 41 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[(lE)-5-methoxypent-1-en-1-yl]phenyl Preparation of }_3_methyl_3,5-diazepine

Step a) Tert-butylpenta- 4-alkynyloxydiphenyl decane to give pentynol (8.0 g, 95 mmol), tert-butyldiphenylphosphonyl chloride (28 g '114 m) The CH2C12 mixture of Et3N and Et3N (14 g, 138 mmol) was stirred at ambient temperature for 16 h, treated with 1M K2C03 and extracted with CH2C12. The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by filtration on EtOAc EtOAc EtOAc (EtOAc: EtOAc) Step b) 2-Amino-5-[4-(difluoromethoxy)phenyl b 5j3_k1E)-5-hydroxypent-1-en-1-yl]phenyl b-3-methyl-3,5 -Dihydro-4H-imidazol-4-one The same procedure as described in Example 40 was used and the title compound was obtained from the title compound. The THF solution containing sulphuric acid (635 mg, 〇·97 mmol) was treated with 1M TBAF in THF (1 mL, 1 mmol), stirred for 16 h, diluted with water and extracted with CH. The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified by EtOAc EtOAc (EtOAc) elute (ih_NMR 300 MHz, DMSO): 7.47 (d, 2H); 7.34_7.14 (m, 4H); 7.16 (t, 1H); 7.11 (d, 2H); 6.68 (s br, 2H); , 1H); 6.19 (dt, 1H); 4.40 (t, 1H); 3.42 (dt, 2H); 2.98 (s, 3H); 2.19 (m, 2H); 1.57 (m, 2H). MS [M+H]+ 416·b Example 42_49-Amine-based oxime^difluoromethoxypentylbu^(4)alkenylphenyl-methyl-dihydro-4-indolizanone

The compounds shown in Table II were obtained using essentially the same procedures as described in Examples 40 and 41 and the desired alkyne of 114619.doc -92-200808735 in step a, and confirmed by NMR and mass spectrometry.

Table II

Example No. R R5 [M+H]+ 42 CH2CH2OCH3 H 430.2 43 〇ch3 H 402.1 44 CH2OCH3 H 416.1 45 CH2OH H 402.1 46 ch2f H 404.1 47 ch2ch2f H 408.1 48 ch2f F 422.01 49 chf2 H 422.1 Example 50 2-Amino- 5-[4-(Difluoromethoxy)phenyl]-5-{3-[2-(methoxymethyl)cyclopropyl]phenyl}·3-methyl-3,5-dihydro Preparation of -4H-imidazol-4-one

114619.doc -93- 200808735 1-ethylzinc (4.923⁄4 liter, 4.92 mmol) in anhydrous CH 2 Cl 2 j 乂 solution at 0 ° C with CF3C 〇 2H (0.56 g, 4_92 mmol) of anhydrous Ch2C12 solution Slowly process, stir for 20 minutes, treat with a solution of CH2l2 (〇66 g, 2 46 mmol) in anhydrous CHKh dropwise, stir for 2 min to contain amidino-5-[4-(difluoromethoxy) Phenyl]_5_{3_[(1e)_3-methoxypropanyl]phenyl}·3-mercapto-3,5-dihydro-4H-imidazole-4-one (197 mg, 0.492 The mixture was treated with aq. CH.sub.2, EtOAc (methanol), EtOAc (EtOAc). The combined extracts were dehydrated with MgSCU and concentrated in vacuo. The residue was purified by EtOAc EtOAc EtOAc. (lH_NMR 3〇〇MHz, DMSO): 7.46 (d3 2H); 7.24-7.13 (m, 3H); 7.16 (t5 1H); 7.10 (d5 2H); 6.88 (m5 1H); 6.64 (s br, 2H) 3.44-3.34 (m5 2H); 3.24 (m, 1H); 3.23 (s, 3H); 2.97 (s5 3H); 1.76 (m, 1H); 0.90- 〇.76 (m, 2H). MS [M+H]+ 416.1. Example 51 2-Amino-5-[4-(dimethoxymethoxy)phenyl]_5_{3_[2-(2-methoxyhexyl)cyclopropyl Iphenyl}-3-methyl-3 Preparation of 5-dihydro-4Η-imidazole- 4-ketone

Use essentially the same procedure as described in Example 50 and use 2•Amino[4-(difluoromethoxy)phenyl]-5-{3-[(10)·4_methoxylated dim small ^ 114619 .doc-94-200808735 yl-3-methyl-3,5-dihydro-4H-imidazol-4-one as a starting material obtained as a white solid title product. 1H NMR: (DMSO d6) δ 7.46 (d5 2H); 7.22-7.13 (m5 3H); 7.16 (dd5 1H); 7.10 (d? 2H); 6.87 (d br, 1H); 6.64 (s br5 2H); (t5 2H); 3.22 (s, 3H); 2.98 (s, 3H); 1.68-1.45 (m, 3H); 〇·97 (m, 1H); 0.76 (m, 2H). MS [M+H]+ 430.1. Example 52 5-(3·Ethylphenyl)-2-amino-5-[4-(difluoromethoxy)phenyl b-3-methyl-3,5-dihydro-4H-imidazole- Preparation of 4-ketone

1) shoulders

2-amino-5-(3-indolyl)-5-[4-(difluoromethoxy)phenyl]_3_methyl-3,5·dihydro-4H-imidazol-4-one (1.50 g, 3.66 mmol), I, bis(diphenylphosphino)propane (DPPP) (〇.377 g, 0.915 mmol), K2C03 (0.606 g, 4.39 mmol), Pd (OAc) ) 2 (82 mg, 〇.37 mmol) and n-butyl vinyl ether (1·47 g, 14.6 mmol) \] \^7/water (8 ml / 0.8 ml) mixture in a microwave oven In 12〇. (:: heating for 1 h, cooling to 'lone, and carefully treated with 153⁄4 liters of 53⁄4 HCl, and scrambled at room temperature for 1 h' diluted with water, basified with K 2 C 3 aqueous solution and extracted with ethyl acetate. The extract was dehydrated with MgSO.sub.sub.sub.sub. cD(:l3) ppm 114619.doc -95- 200808735 8.11 (t,1 H),7.87 (dt,1 H), 7.72 - 7.80 (m,1 H),7.52 (d,2 H),7.44 (t ,1 H),7.08 (d,2 H),6.49 (t,1 H),3·15 (s,3 H)5 2.59 (s,3 H).MS [M+H]+ 374.1 〇Example 53 2-Amino_5_[4_(-methoxymethoxy) benzyl]-5-[3-(3_-yl-hexyl-4- phenan-1-yl)phenyl]·3-methyldiazepine _ Preparation of 4H_Smell

Step a) 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyprop-1-yn-1-yl)phenyl]-3-A 3-,5-dihydro-4H-imidazol-4-one (1) 2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl ]_3-methyl G,5-dihydromyristin-4-one (2.4 g, 5.85 mmol), 3-hydroxy-1-propan (3.27 g, 58.5 mmol) and Pd(PPh3)4 (670 mg, 585 585 mmol) ton of pyridine mixture was heated in 7 (rc and nitrogen for 16 h, diluted with water and extracted with CHK12). The extracts were combined and dehydrated with MgS 〇 4 and concentrated under vacuum 114619.doc -96- 200808735 condensed to obtain a residue. The residue was purified by chromatography on silica gel to give 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3_(3- Hydroxypropyl-indole-alkyne-yl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one, 1 g (yield 45%), was confirmed by NMR and mass spectrum analysis. Step b) 2-Amino-5_[4-(difluorodecyloxy)phenyl b-5-[3-(3-hydroxypropyl)phenyl]_3-methyl-3,5--nitro- 4H- Miso-4-嗣(2) A solution of 1 (1 g, 2.6 mmol) and pt〇2 (5 mg, 1%) in ethanol at 15 psi and on a Parr hydrogenator Of 4 h and filtered through diatomaceous earth. The filtrate was concentrated to dryness under reduced pressure to give 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxypropyl)phenyl]-3-methyl -3,5-Dihydro-4H-imidazol-4-one, 830 mg, confirmed by NMR and mass spectrometry. Step c) Compound 3 A solution of 2 (480 mg) in THF was treated with DMAP (150 mg, 1.23 mmol) and Boc 20 (938 mg, 4.3 mmol) in nitrogen, stirred for 2 h, diluted with water And extracted with CH2C12. The extracts were combined, taken with aq. The residue was dissolved in EtOAc (3 mL) EtOAc (EtOAc) The combined extracts were dehydrated with MgSO.sub.4 and concentrated in vacuo to afford residue. The residue is purified by flash chromatography to give the purified 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-propylpropyl)phenyl] _3_Methyl-3,5-dihydro-4H-imidol-4-one compound, 265 mg (yield 44%). The compound (265 mg, 542 542 mmol) was dissolved in dry CH.sub.2CI.sub.sub.sub.sub.sub. Doc -97- 200808735 Washed with water and brine, dehydrated with MgS〇4 and evaporated to dryness. The residue thus obtained was purified on silica gel to give Compound 3, 170 mg (yield: 64%), which was confirmed by NMR and mass spectrum analysis. Step d) 2-Amino-5-[4-(difluoromethoxy)phenyl b-5_[3 gas hydroxy-hexyl-1-yl)phenyl]-3-methyl-3,5- Dihydro-4H-smell-4-one was treated with Grenner (〇1^1^(1) Reagent 4 (656 μl, 0.3283⁄4 mol) containing 3 (80 mg) under nitrogen at -70 °C. A solution of 0.164 mmol of anhydrous THF, which was taken to dryness EtOAc EtOAc EtOAc EtOAc EtOAc The residue (50 mg) was dissolved in CH.sub.2Cl.sub.sub.sub.sub. Purification by preparative HPLC gave the title product, 15 mg, EtOAc EtOAc (EtOAc: EtOAc: EtOAc: ; 5·20 (d,1H); 4·13 (m,1H); 3.03 (s,3H); 2.62 (m,2H); 1.79 (d,3H); 1·74 (m,2H).MS [M+H]+ 428.1. Example 54 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoroprop-1-yn-1-yl) Phenyl]_3_mercapto_3,5 Preparation of _dihydro·4Η-pyran-4-one

2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-hydroxyprop-1-yn- H4619.doc-98- 200808735 1-yl)phenyl ]-3-Methyl-3,5-dihydro-4H-mouth miso-4-one (300 mg, 0.779 mmol) anhydrous (: 112 (: 12 solution in nitrogen and -40 ° C) DAST (252 mg, 1.56 mmol) was added dropwise, stirred at _40 ° C for 1 h, allowed to warm to room temperature, stirred at room temperature for 16 h, diluted with water, stirred for 3 min. The extracts were extracted with CH.sub.2, EtOAc (EtOAc (EtOAc) %, confirmed by NMR and mass spectrometry. Towel NMR (300 MHz, CDC13) ppm 7_60 (s, 1 H), 7.47 (s, 3 H), 7.32 _ 7.38 (m, 1 H), 7.22 - 7.28 (m, 1 H), 7.04 (d, 2 H), 6.47 (t, 1 H), 5.14 (d, 2 H), 3.10 (s, 3 H). MS [M+H] + 388.1 〇 Example 55-57 2 -amino-5-[4-(difluorodecyloxy)phenyl]_5_[3_(3_substituted)-phenyl-3-methyl-3,5-dihydro-4H-imidazole-4 Preparation of ketone compounds

The compound shown in Table III was obtained using essentially the same procedure as described in Example 14, steps f, g, and h, using the desired halobenzene, and confirmed by hydrazine and mass spectrometry. 114619.doc •99- 200808735

Table III

Example No. R4 mp °C [M+H]+ 55 ch2ch2f 60-63 378 56 COCH2CH2CH2CH2F — 434 57 COCH2CH2CH2F 78-82 420 Example 58 2 -Amino-5-[4-(difluoromethoxy)phenyl] -Preparation of 5-(3-p-phenylphenyl)-3-methyl-3,5-dihydro-4H-imidazol-4-one

Step a) 3-((4-(Difluoromethoxy)phenyl)ethynyl)phenol containing 4-(difluoromethoxy)phenyl iodide (4.70 g) in deoxydimethylformamide solution Treatment with trans-dichlorobis(triphenylphosphine)palladium(11) (244 mg) and copper iodide (11) (66 mg) followed by triethylamine (7.52 ml) in nitrogen 114619.doc-100 After stirring for 5 minutes in 200808735, it was treated with 3-hydroxyphenylacetylene (2.467 g), stirred under nitrogen for 16 h, poured into ethyl acetate and washed with &lt;RTIgt; The organic phase was dried over MgS04 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 40° / EtOAc / hexanes to afford 3-((4-(difluoromethoxy)phenyl)ethynyl) phenol, 5.40 g, 1H NMR (DMSO-d6): δ 9.64 (s? 1H), 7.56 (d5 J= 8.8 Hz, 2H)? 7.27 (t5 J= 73.7 Hz, 1H), 7.17 (d,8·8 Hz, 2H), 7.16 (m, 1H), 6.94 (m, 1H), 6.86 (m, 1H), and 6.77 (m, 1H); MS (ES_) m/z 260. Step b) 1-(4-Difluoromethoxy)phenyl)-2-(3-hydroxyphenyl)ethane-1,2-dione to give 3-((4-(difluoromethoxy)) a mixture of phenyl)ethynyl)phenol (5.0 g) and dichlorobis(acetonitrile)palladium(11) (0.50 g) and dimethyl hydrazine at 140 ° C for 4 h, cooled to room temperature, poured Into the water, stir well for 10 minutes, and extract with a gas imitation. The combined extracts were dehydrated with MgS04 and evaporated to a dark oil. The oil was purified by flash chromatography (10% ethyl acetate / hexane to 20 ° / ethyl acetate / hexane) to give a pale yellow waxy solid. -(Difluoromethoxy)phenyl)-2-(3-hydroxyphenyl)ethane-1,2-dione, 2.75 g, 1H NMR (DMSO-d6): δ 10.02 (s, 1H), 7.95 (d,8·9 Hz, 2H), 7.41 (t, / = 73.0 Hz, 1H), 7.38 (m, 1H), 7.34 (d, = 8.9 Hz, 2H), 7·25 (m, 2H) , and 7.12 (m, 1H); MS (ES〇m/z 292. Step c) 2-Amino-5-[4-(difluoromethoxy)phenyl b- 5-(3-hydroxyphenyl) 3-(3-(difluoromethoxy)phenyl)-2-(3-hydroxyphenyl)ethane, 3-methyl-3,5-diaza-4H-glycol-4-pyrene A mixture of _1,2_dione (2.75 g), N-mercaptopurine hydrochloride (1.237 g) and sodium carbonate (2.20 g) was heated at 85 ° C for 8 h and cooled to room temperature. Evaporate in vacuum. The residue obtained in 114619.doc -101 - 200808735 was dissolved in water and gas. The organic phase was separated, taken up with Na.sub.2SO.sub. The oil was purified by flash chromatography (EtOAc EtOAc) eluting : δ 9.24 (bs5 1H)5 7.42 (d5 J = 8.8 Hz, 2H)? 7.12 (t? J = 74.3 Hz, 1H)? 7.06 (d5 8.8 Hz, 2H), 7.02 (m, 1H), 6·80 (m, 2H), 6.57 (bs, 2H), and 6.56 (m, 1H); MS (APPI) m/z 348. Example 59 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(3-fluoropropoxyl-yl)phenyl l-3-indolyl_3, Preparation of 5-dihydro-4H-imidazol-4-one

2-Amino-5-[4-(difluoromethoxy)phenyl]-5-(3-hydroxyphenyl)-3-methyl-3,5-dihydro-4H-imidazole-4 Anhydrous DMF mixture of ketone (197 mg), 1_iodine-3 fluoropropane (127 mg) and cesium carbonate (240 mg) was stirred at room temperature under nitrogen for 16 h, diluted with chloroform and stirred for 5 min. Filter through a glass fiber 3.1 micron syringe filter. The filtrate was evaporated. The resulting residue was subjected to HPLC; combined with a preparative column of CN phase, gradient elution (8 〇% a/20% B to 20 〇/〇A/80% B, A = hexane; B = (20% 曱) Purification of the alcohol/8 〇〇/0-dichloromethane) to give the title compound as a white crystal, mp 161-162 ° C NMR and mass spectrometric analysis confirmed MS (APPI) m/z 408. 114619.doc -102 - 200808735 Example 60 2_Amino_5_[4_(dimethoxymethoxy)phenyl]_5_(4_败_3- Preparation of hydroxy-phenyl)-3-methyl-3'5-diaza_4H_flavor saliva_4_嗣

The title compound was obtained using essentially the same procedure as described in step 17 of Example 17 and using &lt;RTIgt; 1H NMR (DMSO-d6): δ 9.7 (bs, 1H), 7.39 (d, 8.8 Hz, 2H), 7.12 (t, 74·1 Hz, 1H), 7.06 (d,8·8 Hz, 2H), 7.01 (m, 2H), 6.78 (m, 1H), 6.62 (bs, 2H), and 2.93 (s5 3H); MS (ES+) m/z 365 〇 Example 61-78 2_Amino-5- Preparation of [4_(difluoromethoxy)phenyl]_5-(alkoxyphenylmethyl-3,5-dihydro-4H-imidazol-4-one compound

Use essentially the same procedure as described in Example 59 and use the desired alkyl dentate and the appropriate 2-amino-5-[4-(difluoromethoxy)phenyl]-5-(p-phenyl)- 3-Mercapto-3,5-dihydro-4H-imidazol-4-one was subjected to the hydration, and the compound shown in Table 1 was obtained from 114619.doc-103-200808735, which was confirmed by NMR and mass spectrometry.

Table IV

Instance

No. R mp R5 °C m/z

61 ch2-&lt;] H 151-152 402 62 CH2CH2CH2CF3 H 82-85 458 63 CH2CHF2 H 158-159 412 64 CH2CH2CH2CH2F H 139-140 422 65 CH2CH2CH2OC6H5 H Foam 482 66 CH2CH2CH2CN H Foam 415 67 CH2CH2CHF2 F Foam 424.2 68 h2c- ξι= ch3 F Foam 416.2 69 CH2CH2CH2CH2F F Foam 438.2 70 CH2CHF2 F Foam 428.1 71 ch2ch2ch=ch2 H Foam 72 ch2ch2ch=ch2 F 73 ch2ch2ch2ch=ch2 H 74 (r) -ch2(ch3)ch2ch=ch2 H 75 (s)-ch2(ch3)ch2ch=ch2 H 76 ch2=chch2(ch3)ch2 H 77 ch3c(=ch2)ch2ch2 H 78 ch2=chch2 H Example 79 (5R)- 2-Amino-5-[4.(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy-1-yl)phenyl]-3-methyl- 3,5-dihydro-4H-imidazol-4-one (A) and (5S)-2-amine 114619.doc -104- 200808735 base_5-[4-(difluoromethoxy)phenyl]- Preparation of 5-[4-fluoro-3-(3-fluoropropoxy-1-yl)phenyl]-3-indolyl-3,5-dihydro-4H-imidazol-4-one (B)

Separation of 2-amino-5-[4] by palmar HPLC (using a column-type Chiralcel AD, 5 X 50 cm; mobile phase with 14% ethanol/hexane containing 0.1% diethylamine, 95 mL/min) -(difluorodecyloxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy-1-yl)phenyl]-3-methyl-3,5-dihydro-4H- The racemic mixture of imidazole-4-one gave the titled R-isomer (A) as a foam, which was confirmed by NMR and mass spectrum analysis; [oc]D25 = -14.00. (1% EtOH); MS (ES) m/z 424.1; and foam title S-isomer (B), confirmed by NMR and mass spectrometry; [a] D25 = +15.00. (1% EtOH); MS (ES) m/z 424.1. Example 80 (5R)-2-Amino-5-[3-(2,2-difluoroethoxy)-4-fluorophenylbu 5-[4-(difluoromethoxy)phenyl]indolyl_3 ,5_Dihydro_4jj_imidinone (A) and (5S)_2_ Amino-5-[3-(2,2-difluoroethoxyfluorophenyl]_5_[4_(difluoromethoxy) Preparation of phenyl]_3_methyl_3,5-dihydro-4H-imidazole-4__(B) 114619.doc -105- 200808735

Separation of 2-amino-5-[3-(2, using palm-type HPLC (using a column-type Chiralpak AD-H, 2 x 25 cm; mobile phase with 15% ethanol/hexane containing 0.1% diethylamine) 2-Difluoroethoxy)-4-fluorophenyl]-5-[4-(difluoromethoxy)phenyl]_3-methyldihydromethane-4-ag racemic mixture, obtained as a glass The title R_isomer (A) was confirmed by NMR and mass spectrometry; MS (ES) m/z 428.1; and the title of the foam, S-isomer (B), confirmed by NMR and mass spectrometry; [a] D25 = +15.2. (1% EtOH); MS (ES) m/z 428.1. Example 81 2-Amino-5-{3-[(4,4-difluorobut-3-yl-1-yl)oxy]phenyl}_5-[4-(dimethoxymethoxy)phenyl Preparation of 3-methyl-3,5-dihydro-4H-imidazol-4-one

H2n human 114619.doc -106- 200808735 Step a) l-(4,4-Difluorobut-3-enyloxy)-3-((4-(difluoromethoxy)phenyl-ethynyl) -Benzene will contain 3-((4-(difluorodecyloxy)phenyl)ethyl) hydrazine (900 mg), potassium carbonate (636 mg), Aliquat 336 (4 drops), sodium moth (catalytic amount) And methyl bromide mixture of 4-bromo-1,1-difluoro-1-butene (591 μl) was placed in a pressure reaction vessel, heated at 80 ° C for 15 h, and cooled to room temperature. Diluted with dichloromethane and filtered. The filtrate was concentrated in vacuo. EtOAc mjjjjjj -alkenyloxy)-3-((4-(difluoromethoxy)phenyl)-ethynyl)benzene, 560 mg (yield 46.2%); 4 NMR (m.p. dl): δ 7.51 ( d,··= 8.8 Hz, 2H), 7.24 (m, 1H), 7.10 (m5 1H), 7_08 (d, 8·8 Hz, 2H), 7.03 (m, 1H), 6·87 (m, 1H) ), 6·52 (t, 73·5 Hz, 1H), 4.32 (m, 1H), 3.97 (t, “7 = 6·4 Hz, 2H) and 2.47 (m, J = 6.4 Hz, 2H); MS (ES+) m/z 350 〇Step b) 2_Amino-5_{3-[(4,4-difluoro) But-3-enyl-l-yl)oxy]phenyl[4-(difluoromethoxy)phenyl]·3-methyl-3,5-dihydro-4H-imidazole-4-one The same procedure as described in Example 1, step c, was carried out using ^(4,4-difluorobut-3-enyloxy)_3_((4-(difluoromethoxy)phenyl)ethynyl)-benzene as Starting material, the title compound was obtained as white solid, mp 127. Ms (ES) m/z 436.1. Example 82 2-Amino-5-{3-[(4,4-difluorobut-3-yl)oxy]_4-fluorophenyl}_s_[4-(fluoromethyl)phenyl]- Preparation of 3-methyl-3,5-dihydro-4H-imidazol-4-one 114619.doc -107- 200808735

Nal

Step a) 4-bromo-2-(4,4-difluorobut-3-enyloxy)-1-fluorobenzene will contain 2-fluoro-5-bromophenol (2-40 g), potassium carbonate (2.31 mg) ), Aliquat 336 (5 drops), sodium iodide (catalytic amount) and methyl bromide mixture of 4-bromo-1,1-difluoro-1-butene (1.79 ml) were placed in a pressure reaction vessel and Heat in an oil bath at 82 ° C for 15 h. The reaction mixture was cooled, diluted with EtOAc (EtOAc)EtOAc. The residue was purified by flash chromatography (EtOAc, EtOAc: EtOAc: EtOAc) 1-fluorobenzene, 2.23 g (yield 63%), confirmed by NMR analysis. Step b) 2-Amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxybu-4-fluorophenyl}-difluorodecyloxy)phenyl 3-Methyl-3,5-di-argon-4H-imidazole-4-one was used essentially in the same procedure as described in Example 60 and using 4-bromo-2-(4,4-difluorobut-3-enyloxy) The title compound was obtained as a white solid, mp </RTI> </RTI> <RTIgt; </RTI> <RTIgt; MS (ES) m/z 456.1. Example 83 2Amino-5_[4_(mono-f-methoxy)phenyl b-(4-az-3-pent-4-ylide-1-ylbu3_indolyl_3,5-dihydro_4H - Preparation of imipenone 114619.doc -108- 200808735

Step a) Preparation of 1_Fluoryl_4_Moth-2_pent-4-en-1-ylbenzene THF at -78 ° C under nitrogen and containing 〇·5 Μ 3-butenylmagnesium bromide (6.85 ml, 3.43 mmol) Treated with 2-fluoro-5-iodo-benzaldehyde (0.714 g ' 2.86 mmol) in anhydrous THF stirring solution for 1 min, stir-fry for 5 h to warm it up To _3 〇t: 1 h, the reaction was quenched with saturated ammonium chloride. The combined extracts were dehydrated with MgSCU and concentrated in vacuo. The residue was purified by flash chromatography ( EtOAc EtOAc (EtOAc) Yield 65%). Dissolve a portion of the oil (〇.25 g, 0.823⁄4 mol) in anhydrous dichloromethane and cool to 〇 it to three

Benzene, 〇·18 g (yield 76%).

114619.doc -109- 200808735 1-yl)-3-methyl-3,5-dihydro-4H-imidazole-toxin was used in essentially the same procedure as described in Example 60 and using 戍-4-ene small benzene As a starting material, the title compound was obtained as a pale yellow foam. 416(MH) Example 84 2-Aminobutyl _3_Less group I gas phenyl...4_(dioxalyloxy)phenyl b-3-methyl_3,5-dihydro- 4Η-flavor - Preparation of 4-8^

1) BrMg^z^ 2TbF3 &quot;

Using essentially the same procedure as described in Example 83 and using isopropylmagnesium sulphate in step a, the title product was obtained as a pale yellow foam, mp 55-5 8 ° C, confirmed by NMR and mass spectrum analysis. MS (ES+): 404 (M+H). Example 85 2_Amino-5-[4-(difluoromethoxy)phenyl]_5_[3_(1-hydroxybut-2-yn-1-yl)phenyl]-3-indenyl_3,5 ·Preparation of diar argon_4H-miso-4-indole

114619.doc -110- 200808735 3-[2-(4-Difluoromethoxyphenyl)-containing THF treated with 〇·5 Μ 1-propynylmagnesium bromide at 〇 ° C under nitrogen 2-Oxo-ethinyl]-benzaldehyde (0.1 g '0.33 mmol) in anhydrous DME stirred over 10 min. The reaction was quenched with 0. 5 h. and quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined extracts were dried over Mgs 4 and concentrated in vacuo. The residue obtained is purified by flash chromatography (20% to 40% ethyl acetate / petroleum ether) to afford 1-(4-difluoromethoxyphenyl)-2-[3-(1-hydroxy) But-2-ynyl)phenyl]ethane-1,2-dione, 55 mg (yield 49%). The procedure was essentially the same as described in Example 1, step c, and 1-(4-difluoromethoxyphenyl)-2-[3-(1-pyridin-2-ynyl)phenyl]B was used. The title product was obtained as a pale yellow foamy title product (yield: 69%), which was confirmed by NMR and mass spectral analysis. MS (ES+): 400 (Μ+Η). Example 86 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(l,4-dihydroxybut-2-yn-1-yl)phenyl]-3 -Preparation of methyl_3,5-dihydro-4H-imidazol-4-one

Anhydrous interference containing propargyl alcohol (0.1 g, 1.78 mmol) was treated dropwise at -78 ° C under nitrogen with 1·9 M n-BuLi (1.88 mL, 3.57 mmol) Mixing the gluten solution for 10 minutes 'disturbed 〇·5 h and warmed to 〇°c. In the lower air and air, add 3 ml of this solution to the solution containing 3_[2_('dimethoxymethoxyphenyl)-2-oxo-ethenyl)benzaldehyde (〇·ΐ5g, 〇· 49 millimoles) of water 114619.doc -111 - 200808735 DME disturbing solution. After 1 minute, the reaction mixture was quenched with saturated ammonium chloride. The combined extracts were dehydrated with MgSCU and concentrated in vacuo. The residue was purified by flash chromatography (3 EtOAc /EtOAcEtOAcEtOAcEtOAc (1,4-Dihydroxybutan-2-ylidene)phenyl]ethane], 2-dione, 523⁄4 g (yield 29%). Using essentially the same procedure as described in Example 1, step c, and using difluoromethoxy)phenyl]-2-[3-(1,4-dihydroxybut-2-ynyl)phenyl]ethane-1 2,2-dione (52 g, 0.14 mmol) was obtained as a pale brown foamy title compound (yield: 52%). MS (ES+): 416 (M+H). Example 87 2-Amino-5-[4-(difluoromethoxy)phenyl]_5_[3_(2,2-dimethyl-7-oxocyclobutyl)phenyl b-3-yl_ Preparation of 3,5-dihydromyristone

Step a) 3_(3·-Phenyl-phenyl)-2,2-dimethyl-cyclobutanone is treated with trifluoromethanesulfonic anhydride via a syringe under nitrogen at -13 C, containing N, N, 2_3 Mercaptopropylamine (3.65 g, 31·7 mmol) and di-methane methane 114619.doc -112- 200808735 solution, stirred for 10 minutes to contain 3-bromostyrene (5·〇4 g, 27.6毫mol) and 2,4,6-trimethyl acridine (4·32 g, 35·7 mmol) ch^c! 2 solution was treated dropwise for 40 minutes and heated at reflux temperature 2〇 h, cooled to room temperature and concentrated in vacuo. The concentrate was diluted with water and CH2Cl2 and heated at 89 for 7 h. After cooling to room temperature, the phases were separated and the aqueous phase was extracted with CH. The organic phase and extract were combined, dried over NajEtOAc, and evaporated. The resulting concentrate was purified by column chromatography ( gradient 5% - 10% EtOAc hexane) to afford 3-(3-bromophenyl)-2,2-didecyl- ring. Butanone, 4.26 g (yield 61%); 1H NMR (400 MHz, DMSO-A) δ ppm 0.69 (s, 3 H) 1·25 (s, 3 Η) 3.24 (dd, "7=17.4, 9 · 0 Hz, 1 Η) 3·44 (t, &gt;8·9 Hz, 1 Η) 3.64 (dd3 /=17.3, 8.7 Ηζ? 1 Η) 7.23 - 7.35 (m, 2 Η) 7.43 - 7·47 (m,1 Η) 7.49 (s,1 Η). Step b) 2-Amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(2,2-dimethyl-oxocyclobutyl)phenyl]-3 _Methyl-3,5-dihydro-4 oxime-imidazol-4-one was used essentially in the same procedure as described in Example 17, step d, and 3-(3- chlorophenyl)-2,2-dimethyl- Cyclobutanone as the starting compound gave mp 172-174 ° C; NMR (400 MHz, DMSOd6) δ ppm 〇·61 (s,3 Η) 1·21 (s,3 Η) 2.98 (s,3 Η) 3·19 _ 3·28 (m,1 Η) 3-34 - 3·40 (m,1 Η) 3·41 - 3·47 (m, household 4.9 Ηζ, 1 Η) 6.71 (s, 2 Η) 6·96 - 7·19 (m, 4 Η) 7·24 - 7·37 (m, 3 Η) 7·44 (d, J=7.9 Ηζ, 2 H); MS (ES m/z 426·2 [Μ-Η]-; HRMS·· C23H23F2N303+H+, calculated 428· 17802; found (ESI, [Μ+Η]+), 428.1780. Example 88 2-Amino-5-[4-(difluoromethoxy)phenyl]_3_indolyl-5_[3-(3•oxocyclobutene 114619.doc-113-200808735-yl)phenyl] Preparation of -3,5-dihydro- 4H-flavor saliva_4_嗣

Using the same procedure as described in Example 87 and using N,N-dimethylacetamide in the procedure &amp;&lt;&gt;&gt; MHz, DMSOd6) δ ppm 2·97 (s,3 Η) 3.06 - 3.17 (m,2 Η) 3·36 - 3.46 (m,2 Η) 3.59 (q,*/=7·3 Hz,1 Η) 6.68 (s, 2 Η) 7·10 (d, *7=8.8 Ηζ, 2 Η) 7·16 (t, /=74.2 Ηζ, 1 Η) 7.23 - 7.34 (m, 3 Η) 7.39 - 7.50 (m MS (ES) m/z 398.1 [MH]-; HRMS: &lt;RTI ID=0.0&gt;&gt;&gt;&gt; Example 89 2-Amino-5-[4-(difluoromethoxy)phenyl 5-[3-(3-hydroxy-cyclobutyl)phenyl]_3-methyl-3,5-diargon Preparation of -4H-imidazol-4-one

114619.doc -114- 200808735 2-Amino-5-[4-(difluorodecyloxy)phenyl]_3_A was treated once as NaBH4 (0.042 g, 1.ii mmol) at ice bath temperature Base _5_[3_(3• oxocyclobutyl)benzyl]-3,5-monohydro-4Η_ϋ米嗤-4- ketone (0.324 g, 0.811 mmol) in methanol solution 〇°°C Stir for 45 minutes and concentrate in vacuo. The solid residue was dissolved in water and chloroform. The organic phase was separated, dehydrated with sodium sulfate and evaporated to a foam. The foam was dissolved in chloroform and precipitated with hexane to give a white solid compound: 0.307 g (yield 94%), mp 186-190 ° C; lU NMR (400 MHz 5 DMSO-J6) δ ppm 1.70 - 1.86 (m5 2 H) 2.53 - 2.60 (m, 2 H) 2.70 2.85 (m,1 Η) 2·97 (s,3 H) 3.89 - 4.08 (m,1 H) 5.08 (t,/ =5.2 Hz,1 H) 6.69 (s,2 H) 7.10 (d,J=8.6 Hz,3 H) 7.17 (t,/=74.2 Hz,1 H) 7.19 - 7.33 (m,3 H) 7.45 (d , J = 8.8 Hz, 2 H); MS (ESI) m/z: 400.2 [MH]························· Example 90 [3_(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazole- Preparation of ethyl 4-phenyl}phenyl)cyclobutylene

114619.doc -115- 200808735 Step a) [3-(3-Bromophenyl)cyclobutylene]ethyl acetate to make each 3_(3·bromophenyl)cyclobutanone (2.03 g, 9·02 mmol) Ear) and methylene chloride solution of tnphenylph〇sph〇ranylidme acetic acid (15.72 g, 45·12 mmol) in cEMDisc〇verTM microwave and 12〇◦ The next radiation is 3 minutes. The pressure reaches a maximum of 18 psi. , 2, and 2, followed by column chromatography (equal gradient; 10% diethyl ether in hexane) to give an oily [3-(3-bromophenyl)cyclobutylene]ethyl acetate , 2·37 g (yield 89%), m NMR (4 〇〇 MHz, dms 〇〇谷冲(7) ^ (t, /-7·1 Hz, 3 Η) 2·89 - 3.00 (m, 1 Η ) 3·03 - 3.11 (m,1 Η) 3.16 -3.27 (m,1 Η) 3·46 _ 3.57 (m,1 Η) 3.63 (q,/=8.0 Ηζ,1 Η) 4.08 (q,/= 7.0 Ηζ, 2 Η) 5·71 (q, /=2·9 Ηζ, 1 Η) 7·25 - 7·35 (m, 2 Η) 7·39 - 7.43 (m,1 Η) 7_48 - 7.52 ( m,1 H); MS (APPI) m/z 295 [Μ+Η]+ 〇Step b) [3_(3-{2-Amino-4-[4-(difluoromethoxy)phenyl) iotamethyl_5_oxo-4,5-dihydro-1Η-imidazol-4-yl}phenyl)cyclobutylene]ethyl acetate was used essentially in the same procedure as described in Example 17 Step d, and used [ Ethyl 3-(3-bromophenyl)cyclobutylideneacetate afforded the title compound as a white powder, mp 78-80 ° C; NMR (400 MHz, DMSO-A) δ ppm 1.19 (t, 7· 1 Hz,3 Η) 2·78 - 2.89 (m,1 H) 2.97 (s,3 H) 3.02 - 3.07 (m,1 Η) 3·16 - 3.26 (m,1 H) 3_45 - 3·53 (m,1 H) 3.55 - 3.66 (m,1 H) 4.07 (q5 J=7.0 Hz5 2 H) 5.64 - 5.75 (m? 1 H) 6.67 (s5 2 H) 7.05 -7.11 (m5 2 H) 7.16 (t5 J=74.2 Hz5 1 H) 7.17- 7.21 (m, 1 H) 7.23 - 7.33 (m,2 H) 7.37 (s,1 H) 7.43 - 7.51 (m,2 H); MS (ES m/z 468.1 [MH] — 114619.doc -116- 200808735 Example 91 [3-(3-{2·Amino{{Heart (di-g-oxy)phenyl] small methyloxo- 4 ,5_Nitrogen-1H-flavory-4-ylindole phenyl)cyclobutylene]methyl acetate preparation

A foamy title product was obtained using essentially the same procedure as described in Example 90 and using triphenylphosphoric acid ethyl acetate in step a. NMR analysis showed the foam to be a 7:3 mixture of methyl ester and ethyl ester. 1H NMR (400 MHz, DMSO oxime, a mixture of methyl ester and ethyl ester (7:3) δ ppm 1.15 -1·23 (m, ethyl ester 3 Η) 2.76 - 2.91 (m,1 Η) 2.97 (s, 3 Η) 2.99 · 3.07 (m,1 Η) 3·11 - 3.27 (m,1 Η) 3·42 - 3·55 (m,1 Η) 3·55 - 3·60 (111,111)3.61 ( 8, decyl ester 3 11) 4.01-4.12 (111, ethyl ester 2 11) 5.64 - 5.77 (m, 1 Η) 6.68 (s, 2 Η) 7·10 (d, J = 8.8 Ηζ, 2 Η) 7.16 (t, 7=74.2 Ηζ5 1 Η) 7.18 - 7.22 (m5 1 Η) 7.23 - 7.33 (m5 2 Η) 7.35 -7.38 (m, 1 Η) 7.46 (dt? /=9.2, 2.6 Hz, 2 Η) MS (ES) m/z 454.1 (Me) [MH]-; MS (ES) m/z 468.1 (Et.) [MH]-. Example 92 114619.doc -117- 200808735 [3-(3- (2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl·5-oxo-4,5-dihydro-1H-imidazole-4-yl}phenyl) Preparation of methyl cyclobutyl]acetate

F Step a) Preparation of methyl (3_{3-[2·(4-difluoromethoxyphenyl)-1,2-dihydroxyethyl]phenyl}-cyclobutyl)acetate will contain 10% Pd/C (0.092 g) and (3-{3-[2-(4-difluoromethoxyphenyl)-2-oxoethyl)-phenylcyclobutylidene)methyl acetate (0.78) The gram, 1.95 millimolar ethanol mixture was placed in a 15 PSI hydrogen Parr hydrogenator for 3 hours. Add more 10% Pd/C (0.056 grams) and place the shaker under 30 PSI hydrogen for 2 h. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo to give (3-{3-[2-(4-difluoromethoxyphenyl)-i,2-dihydroxyethyl]phenyl}-cyclobutyl)acetate as an oil, 402克 (yield 51%); 4 NMR (400 MHz, DMSO-A) δ ppm 1.67 (q, J = 9.1 Hz, 1 Η) 1.92 - 2.07 (m5 1 H) 2.13 - 2.23 (m, 1 H 2.32 - 2.44 (m,3 H) 2.56 - 2.64 (m,1 H) 3.35 · 3.44 (m,1 H) 3.55 - 3.65 (m,3 H) 4.45 - 4.63 (m,2 H) 5.08 114619.doc -118- 200808735 -5·38 (m,2 Η) 6·56 _ 7·43 (m,9 H); MS (ES) m/z 405.1 0 Step b) 1-(4-Difluoromethoxy Phenyl)-2-[3-(3-oxocyclobutyl)-phenyl]ethane-1,2-dione to give 1M o-iodooxybenzoic acid (IBX) to dmSO (0.90 ml) Solution and methyl (3-{3·[2-(4-difluoromethoxyphenyl)-12-dihydroxyethyl]phenylcyclobutyl)acetate (0.144 g, 0.354 mmol) The mixture was stirred for 30 minutes' treatment with an additional 1.23⁄4 liters of DMSO containing 1 M IBX, scrambled for 15 minutes, and dissolved in water and diethyl ether. The organic phase was separated, dehydrated with Na2S〇4 and vacuumed. The residue was purified by column chromatography (丨〇% hexane ethyl acetate) To obtain 1-(4-difluoromethoxyphenyl)-2-[3_(3-oxocyclobutyl)-phenyl]ethane-1,2-dione as an oil, 0133 g Rate 93%); lH nmr (400 MHz, DMSO 〇 δ ppm m ! 87 plus, 2 H) 2 〇6 _ 2 i7 (4) 1 Η) 2.26 (s? 1 Η) 2.55 - 2.69 (m, 2 Η) 3.46 (s5 1 Η) 3.54 - 3.62 (m, 3 Η) 3.73 (s5 1 Η) 7.23 - 7.82 7 Η) 7.95 - 8.06 (m, 2 H); MS (ES) m/z 403·0 [Μ+Η ]+. Step C) [3_(3_{2·Amino·4_[4_(difluoromethoxy)phenyl]小methyl-5-oxo-4,5-dihydro-1Η-味嗅-4_ Methyl}phenyl)cyclobutyl]methyl acetate was used essentially in the 4-phase sequence described in Example 1, Step C and using 1-(4-difluoromethoxyphenyl)-2-[3-(3) -Oxocyclobutyl)volume)-propenyl]ethane-12-dione as starting material' gave a white solid titled mantle, mP 08-70. (: (foam); H NMR (400 MHz, DMSO 〇 δ ηη , ^ PPm 1.63 - 1.76 (m, 2 Η) 1.98-2.04 (m3 1 Η) 2.11 - 2.18 (m, IH) ?) 2.36 - 2.46 (m5 4 Η) 2.58 - 2·65 (m, 2 Η) 3·02 (s, 3 Η) 3.54 - 3 , ·62 (m,3 Η) 7.10 - 7·17 (m, •7=7.6 , 7.6 Ηζ,3 Η) 7·19 (t,&gt;74 1 Μ 1 τ • Ήζ,1 Η) 7·21 - 7.31 (m,3 Η) 114619.doc -119- 200808735 7.41 - 7·47 ( m,2 H); MS (ES) m/z 456.1 [μ_Η]_. Example 93 2-Amino group [3-(di- gas T-oxy)phenyl]·5_[Μ:fluoro-oxy)benzene Preparation of mercaptodihydro-4H-imidazolone

A white foam-like title was obtained using essentially the same procedure as described in Example 18, step d, using 4-difluoromethoxy bromide and 1-difluoromethoxy-3-ethynyl-benzene as starting materials. Compound, mp 52_54t:; lH Nmr (4(^ MHz, DMSO-A) δ ppm 2.98 (s,3 Η) 6·75 (s,2 Η) 6·96 7.13 (m,3 Η) 7·17 ( d, "7=2.9 Ηζ,1 Η) 7·24 (s,1 Η) 7 33 7.38 (m, 3 Η) 7.48 (d5 J=8.8 Hz, 2 H); MS (ES) m/z 398.1 [ M+H]+ 〇Example 94 (58)-2-Amino-5-[3-(difluoromethoxy)phenyl 5-[4-difluoro-methoxy]phenyl]methyl- 3,5_Dihydro-4 Η·imidazolone (a) and (5R)_2-amino _5-[3_(difluoromethoxy)phenyl]-5_[4-(difluorodecyloxy)benzene Preparation of methyl]methyl-3,5-dihydro-4H-imidazol-4-one (B) 114619.doc • 120 - 200808735

2-Amino-5-[3-(difluoromethoxy)phenyl]-5-[4-(difluoro-indolyloxy)phenyl]-3-methyl-3,5-dihydro The racemic mixture of -4H-imidazol-4-one is placed in 〇1 to 1〇610夂2 parent 25 (:111 column (dissolved solution: 1〇〇/0£{〇only burned / 0£8, The material was collected at 6.14 minutes (product A) and 7.42 minutes (product B). The separated enantiomers were concentrated by rotary evaporator, diluted with ethanol and re-concentrated to obtain an oily residue. The oily residue was diluted with diethyl ether and an equal volume of hexane and concentrated to give the title compound as a white solid: A (118 mg) and B (96 mg). Peptide, [a] D25 = 8.6. (c = 1% MeOH); 4 NMR (400 MHz, DMSO-A) a ppm 2·98 (s, 3 Η) 6·75 (s, 2 Η) 6· 96 _ 7.13 (m,3 Η) 7.17 (d, J=2.9 Ηζ, 1 Η) 7·24 (s,1 Η) 7·33 - 7·38 (m,3 Η) 7·48 (d,/ = 8.8 Hz, 2 H); MS (ES) m/z 396.1 [Μ·Η]-; and confirmed product Β as (R)-enantiomer, [a]D25=-8.2. (c=l% MeOH 4 NMR (400 ΜΗζ, DMSO-A) δ ppm 2.98 (s, 3 H) 6.75 (s, 2 H) 6.9 6 - 7.13 (m,3 H) 7.17 (d, 7=2.9 Hz, 1 H) 7.24 (s5 1 H) 7.33 - 7.38 (m5 3 H) 7.48 (d, /=8.8 Hz, 2 H); MS ( ES) m/z 398.1 [M+H]+. Example 95 114619.doc -121-200808735 2-Amino- 5-[4-(difluoromethoxy)phenyl]-5-{3-[( Preparation of lR)-l·fluoropent-4-iso-1-yl]phenyl}_3_methyl_3,5-dihydro-4H-imidazol-4-one

Step a) (3-Bromophenyl)acetaldehyde The lead tetraacetate was treated with a solution of 1-bromo-3-vinylbenzene (1.5 g, 8.2 ml) in dichloromethane at 〇C. a mixture of gram, 8.2 mmol, and trifluoroacetic acid (8.25 ml), allowed to warm to room temperature, stirred at room temperature for 2 h, diluted with dichloromethane, poured into water, stirred vigorously and passed through celite Padded. The filtrate was separated. The filter cake was washed with an additional portion of dichloromethane. The combined organic phases were washed sequentially with water, NaHCCh and brine, dried with EtOAc EtOAc. Step b) (R)_2_Fluoro-2_(3_bromophenyl)acetaldehyde (References • MacMillan and Beeson, JACS 2005, 127, 8826) (3·Bromophenyl)acetaldehyde at room temperature ( 280 mg, 1.4 mmol, treated with (5R)-5-benzyl-2,2,3-trimethylimidazolidin-4-one diacetoacetate (97 mg, 0.43⁄4 mol) and Fluorobenzene phthalamide (3·15 g, 10 mmol) _ H4619.doc -122- 200808735 9.1 mixture with isopropanol, stirred at room temperature for 1 匕, cooled to -78 ° C Dilute with diethyl ether and filter through a pad of Celite. The filter cake was washed with additional ether. The combined filtrate was treated with methyl sulfonium (5 ml), washed with saturated NaHC 〇 3 and brine, dried with EtOAc (EtOAc) and concentrated under reduced pressure to give (R)-2 fluoro-2 . Step c) toluene-4-sulfonic acid (S)-2-(3-bromophenyl)_2-fluoro-ethyl ester containing (8)·2-fluoro-2-(3-bromophenyl)acetaldehyde ch2C12 and The solution of ethanol was treated with NaBH4 (189 mg, 5 mmol), stirred for 3 hrs, cooled to 0 C, treated with saturated NH/l, warmed to room temperature, stirred vigorously at room temperature for 1 h and diluted with CH2C12 . Separate the phases. The aqueous phase was extracted with ch2C12. The combined organics and extracts were washed with EtOAc EtOAc m. The residue was purified by column chromatography ( EtOAc EtOAc EtOAc) In the ice bath temperature, stir it down. A solution containing (R)-2-fluoro-2-(3-bromophenyl)-1.ethanol (5 mmol) and p-nonylbenzenesulfonate (51 mmol) was treated. The reaction mixture was heated at reflux temperature under nitrogen for 16 h, cooled to room temperature, washed with 1 EtOAc / EtOAc EtOAc EtOAc EtOAc EtOAc _2_(3_Bromophenyl)_2_fluoro-ethyl ester. Step d) 1_Bromo-(8)-3_(1_fluoropent-4-ene-;^ base) stupidly treated with toluene_4_ at room temperature with a solution of allylmagnesium bromide A solution of succinic acid (S) 2 -(3-bromophenyl)-2-fluoro-ethyl ester (5 mmol) in THF, stirred at room temperature for 5 h, quenched with saturated N? B_ extraction. The combined extracts were washed with water and brine, dried with Mgs 〇 4 and concentrated in vacuo at 114619.doc -123-200808735 to obtain 1-bromo-(S)-3-(l•fluoropent-4-ene-1 -based) benzene. Step e) 2_Amino-5-[4-(difluorodecyloxy)phenyl]_5_{3_[(ir)_i_Aceton-4-en-1-yl]phenyl}-3-A Benzyl-3,5-dihydro-4H_pyrene_4-_ using essentially the same procedure as described in Example 14, steps f, g and h, and using 1-bromo-(S)-3-(bufluoropentane- 4-Indol-1-yl)benzene was used as the starting material to give the title product, which was confirmed by NMR and mass spectrum analysis. Example 96 2-Amino_5-[4-(difluoromethoxy)phenyl]_5-{3-[(lR)_;U-fluorobutyl]phenyl}-3-methyl·3,5 -Preparation of dihydro- 4 Η· miso-4_ ketone

Using essentially the same procedure as described in Example 95 and using vinylmagnesium bromide in step d, the title compound was obtained and confirmed by NMR and mass spectrometry. Example 97 N-(3-{2-Amino-4-[4 Preparation of -(difluoromethoxy)phenyl b-methyl_s_oxo$ diar-argon-1H-imidazol-4-yl}phenyl)ethanesulfonamide 114619.doc -124- 200808735 1) ΚΜΝ〇4, NaHC〇3 MgS04,: acetone, Η20

Step a) N-(3-{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)ethane decylamine with ethyl sulphate chloride (0·27 ml, 2.89 mmol) CH2C12 cooling with 0_{[4_(difluoromethoxy)phenyl]ethynyl}aniline (0.5 g, 1.93 mmol) and 0-pyridine (0.31 mL, 3.80 mmol) was treated dropwise (0) The solution was stirred for 5 hours, poured into water and extracted with EtOAc / EtOAc EtOAc.EtOAc. / EtOAc (3 / 1) was purified as a solvent to give y-(3·{[4-(difluoromethoxy)phenyl]ethynyl}phenyl)ethanesulfonamide as a yellow oil (0·62) g) Step b) Ν-(3·{2-Amino-4-[4-(difluoromethoxy)phenyl i-methyl-5-oxo-4,5-dihydro-1H -Mimi-4-yl}phenyl)ethylidene amine was used essentially in the same procedure as described in Example 12, steps c and d, and using Ν-(3-{[4-(difluoromethoxy)phenyl) As a starting material, ethynyl}phenyl)ethanesulfonamide was obtained as a white solid title compound. [M+H]+439.1. Example 98_108 N-(3-{2-Amino-4·[4_(difluoromethoxy)phenyl)1_methyl_5_oxo·4,5-114619.doc -125- 200808735 Dihydrogen Preparation of -1H-imidazol-4-yl}phenyl)sulfonamide compound

1) KMN〇4, NaHC〇3 MgS04, acetone, h2〇 h2n pn3 o2s-n

2) NH

A H2N NHMe The compound shown in Table V was obtained using essentially the same procedure as described in Example 97 and using the desired sulfonium chloride in step a, and confirmed by NMR and mass spectral chromatography.

Table V

Example No. R [m+h]+ 98 3,4-Difluorophenyl 523 99 3-methoxyphenyl 517.1 100 3-chlorophenyl 521 101 n-propyl 453.1 102 3-cyanophenyl 512.1 103 3-(Trifluoromethoxy)phenyl 571.1 104 3-pyridyl 488.1 114619.doc -126- 200808735 105 4-cyanophenyl 512.1 106 2-σsecenyl 493 107 benzyl 501.1 108 3,5- Difluorophenyl 523.1 Example 109-112 ^(3-{2-Amino-4-[4-(difluoromethoxy)phenyl]-1-methyl-5-oxo-4,5-dihydrogen Preparation of -1H-imidazol-4-yl}phenyl)acetamide compound

1) KMN〇4, NaHC〇3

The compound shown in Table VI was obtained using essentially the same procedure as described in Example 97 and using the appropriate chlorobenzene in step a, and confirmed by NMR and mass spectrometry. The palmar separation was achieved using essentially the same procedure as described in Example 1, step d. 114619.doc -127- 200808735

Table VI

Example number versus palmity RR, [Μ+Η] 109 — CH2OCH3 Η 419.1 * 110 — ch2och3 ch3 433.1 111 4-R CH20CH3 Η 419.2 +19.2 112 4-S CH20CH3 Η 417.3** -15.2 * 1 % methanol solution example 113 2-amino-5-[4-(difluorodecyloxy)phenyl b-[3-(5-hydroxypent-1-yn-1-yl)phenyl]-3-methyl-3, Preparation of 5-dihydro-4H-imidazole-4-ketone

OH

2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-411-imidazole-4 -ketone (1.15 g, 2.8 mmol), dioxane, bis(benzonitrile) di-palladium (11) (32.2 mg, 0.084 mmol), tri-tert-butyl 114619.doc -128 - 200808735 Mixture of phosphine (10% w/w in hexane, 339 mg, 〇·ΐ7亳 Mo) and diisoamine (340 mg, 3.36 mmol) in argon for $ min: ___ Treatment with alkyn-1-ol (236 mg, 2.8 mmol), stirring at 8 (rc) for 5 h, poured into water, and extracted with ethyl acetate. combined with extracts, dehydrated with MgS 4 and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) Preparation of 5-[4-(difluoromethoxy)phenyl 5-(3-ynylphenyl)_3_methyl-3,5-dihydro-4H-imidazolone compound

The compounds listed in Table VII were obtained using essentially the same procedure as described in Example 113 using the desired acetylene reagents and confirmed by NMR and mass spectrometry. The palm separation was achieved using essentially the same procedure as described in Example 1, step d. 114619.doc -129- 200808735

Table VII

Example number versus palm R R5 [Μ+Η] [α]* 114 — ch2ch2ch2f Η 416.1 115 — CH2CH2CH2C1 Η 432 116 ~ CH2CH2CH3 Η 398.1 117 ~ CH2CH20H Η 400.2 118 CH2CH2CH2CH20H Η 428.2 119 — CH2CH2CH2CH2F Η 430.2 120 ~ CH2CH2C1 Η 418 121 5-R CH2CH3 Η 398 +12.8 122 5-S CH2CH3 Η 398 -9.8 123 5-S CH2CH2CH20H Η 414.1 +12.4 124 5-R CH2CH2CH2CH20H Η 428 +10.2 125 5-S CH2CH2CH2CH20H Η 428 -11.4 126 5-R CH2CH20H Η 400 127 5-S CH2CH20H Η 400 13 128 5-S CH2CH2CH2F Η 416.1 -11.4 129 5-R CH2CH2CH2F Η 416.1 +19 130 5-S CH2CH2CH20H F 432.1 +11.6 131 5-R CH2CH2CH20H F 432.1 132 5-S CH2CH2CH2F F 432.1 +8.6 133 5-R CH2CH2CH2F F 434.2 -8.4 134 ~ CH2CH20CH3 Η 414.1 135 ~ CH20CH3 Η 400.1 136 5-S CH2CH20CH3 Η 414.2 -12 114619.doc -130- 200808735 Table VII (continued)

Example number versus palm R R5 fM+Hl 137 5-R CH2CH2OCH3 Η 414.2 138 — CH2CH2F Η 402.2 139 — ch2ch(ch3)2 Η 412.2 140 CH(OH)CH2CH3 Η 414.1 141 CH2CH(OH)CH3 Η 414.2 142 — CH (CH3)2 Η 398.1 143 — CH2CH3 Η 384.2 144 — CH2CH2CH2CH3 Η 412.2 145 — Cyclopropyl hydrazine 396.2 146 — Cyclohexyl hydrazine 438.2 147 -- Cyclopentyl hydrazide 8.2 438.2 148 — Cyclohexyl hydrazide 2.2 452.2 149 5- S CH2OCH3 Η 400 150 5-R CH20CH3 Η 400 151 — CH20CH3 F 418 152 — CH2CH20CH3 F 432 153 — ch2oh Η 386.1 154 — (s)-ch(oh)ch3 Η 400.1 155 — (R)-CH(OH)CH3 Η 400.1 156 — ch(oh)ch(ch3)2 Η 428.2 157 — 1-hydroxycyclopentyl Η 440.2 158 — 1-hydroxycyclohexyl Η 454.2 Μ +10.6 -6.8 114619.doc -131 - 200808735 Table VII )

Example number versus palm R R5 [M+H] 159 __ c(oh)(ch3)2 H 414.2 160 — C(OH)(CH3)CH2CH3 H 428.2 161 — Η H 356.1 162 — (S)-CH(OH C6H5 H 462.1 163 5-S ch2ch2och3 H 432 +7.8 164 5-R CH2CH20CH3 H 432.1 -6.6 165 5-S CH20CH3 H 418.1 166 5-R CH20CH3 H 418.1 167 — ch3 F 388.1 168 — ch3 H 370.1 169 5-R (S)-CH(OH)CH3H 400.1 -19.2 170 5-S (S)-CH(OH)CH3 H 400.1 171 5-R ch3 H 370.1 -15.6 172 5-S ch3 H 370.1 +15 173 5-R Ch2ch2ch2oh H 414.1 *1% methanol solution Example 174 2-Amino-5-{3-[(E)-2-cyclopropylvinyl]phenyl}-5-[4-(difluorodecyloxy)benzene Preparation of benzyl-3-methyl-3,5-dihydro-4H-imidazol-4·one 114619.doc -132- 200808735

2-Amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]-3-methyl-3'5-monohydro-4H-imiline-4 -ketone (150 g, 0.36 mmol) 'Dimethoxyethane, 2-[(E)-2-cyclopropylvinyl]-4,4,5,5-tetradecyl-l53,2 a mixture of _dioxolane (105 mg) and NkCO^ (2.5 ml) was degassed in argon for 5 minutes and was purified by tris(triphenylphosphine)palladium (21 mg, hydrazine). 〇18 millimoles). The reaction mixture was stirred for 15 h, poured into water and extracted with ethyl acetate. The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified with EtOAc EtOAc EtOAc (EtOAc) Example 175-187 2-Amino-5-[3-(2-substituted-vinyl)phenyl b-[4-(difluoromethoxy)phenyl]methyl-hydrogen_4Η- miso Preparation of _4_嗣 compound

Or OCHF〇 R·

PdClXP-tolyl 3) 4), dee

L-order, and using the vinyl bis' to obtain the formulation listed in Table VIII using essentially the same procedure as described in Example 174, borane or vinyltributyltin reagent, 114619.doc • 133. 200808735, and Confirmed by NMR and mass spectrometry.

Table VIII

Example No. R R' R,, R5 [M+H] 175 ch3 HHH 372.1 176 ch3 HHF 390.1 177 Η HHH 358.1 178 ch3 ch3 HF 418 179 Η H ch3 H 372.1 180 CH2CH2CH3 HHH 400.2 181 CH2CH2CH2CH2CH3 HHH 428.2 182 CH2CH2CH2C1 HHH 434.1 183 C6h5 HHH 434.2 184 2,4-difluorophenyl HHH 470.1 185 ch2ch2ch2ch2ch2ch3 HHH 442.2 186 HH c6h5 H 434.1 187 CH2CH2CH2CH3 HHH 414.2 Example 188 BACE-1 Binding Affinity Evaluation of Test Compounds Fluorescence Dynamic Analysis Final Analysis Conditions: 10 nM Human BACE1 (or 10 nM murine BACE1, 1.5 nM human BACE2), 25 μΜ receptor (WABC-6, MW 1549.6, obtained from AnaSpec), buffer: 50 mM sodium acetate, pH 4.5, 0.05% CHAPS, 25% PBS, room temperature. Sodium acetate was purchased from Aldrich, batch 114619.doc-134-200808735 times #24,124-5, CHAPS was purchased from Research Organics, lot number #1304C IX, PBS was purchased from Mediatech (Cellgro), lot number #21- 031_CV, peptide peptide AbzSEVNLDAEFRDpa was purchased from AnaSpec, peptide name: WABC-6 liquid substrate (AbzSEVNLDAEFRDpa) concentration determination: using peptide weight and MW in DMSO to make about 25 mM stock solution and in IX PBS Dilute to about 25 μΜ. The concentration was measured by the extinction coefficient ε of 18172 M'm·1 by the absorbance at 354 nm, the stock solution concentration was corrected, and the substrate solution was stored in a small amount at -80 °C. [Accumulating liquid] = ABS3 54nm* 106/18172 (WmM^) The extinction coefficient s3 54nm was taken from the TACE peptide acceptor, which has the same culturizer-phosphor pairing. The concentration of the liquid enzyme was measured: ε was 64150 for hBACE1 and MuBACE1 and ε was 628701^-1^^1 for 6B rust hydrochloride (purchased from Research Organics, lot number #5134G-2) for hBACE2 (pH approx. 6) Determine the concentration of plastics in each school by the absorbance at 280 nm. Calculate the extinction coefficient of each enzyme based on the known amino acid composition and the disclosed Trp extinction coefficient (5.69 Μ'ιϊΓ1) and Tyr extinction coefficient (1·28 M·1 cm·1). s28Gnm〇4 such as /· 5 / Shen ~ mouse 182, 319-326). Dilution and mixing steps: Total reaction volume: 100 μl in buffer A (66.7 mM sodium acetate, pH 4.5, 0.0667% CHAPS) Final preparation of 2X inhibitor dilution in buffer Α (66·7 mM sodium acetate, pH) 4.5,0.0667% CHAPS) Final Preparation 4X Enzyme Diluent, 114619.doc -135· 200808735 Prepare 100 μΜ of the substrate dilution in 1 PBS, and add 500 μl of 2Χ inhibitor, 25 μl of 100 μΜ substrate to In each well of a 96-well plate (purchased from DYNEX Technologies, VWR #·· 11311-046), 25 microliters of 4X enzyme (added to the inhibitor and substrate mixture) was immediately added and the fluorescence was read. Fluorescence reading was performed every 30 seconds at room temperature, reading of ^2〇11111 and 〇142〇11111 for 30 minutes and measuring the linear slope of the yield fracture rate (Vi). Calculation of % inhibition: suppression %=100*(1-Vi/V.)

Vi = rate of failure at the presence of inhibitor νο = rate of failure at 1C 50 in the absence of inhibitor: (Model #39 was obtained from LSW τ〇〇1 in Excel, where B is derived from _ % inhibition in the control group, which should be close to 〇). The % inhibition is plotted against the inhibitory shoulder (I.) and the data is set in the above procedure to obtain the %" and (iv) values of each compound (8). It is preferred to test at least one different inhibitor concentration. The results are shown in Table IX. In Table IX A - &lt;0.01 μΜ-0.1〇 μΜ Β = 〇·11 μΜ-1·00 μΜ C = &gt;1.00μΜ 114619.doc -136- 200808735

Table IX BACE-l instance number IC5〇 μΜ

ΙΑ B IB C 2 B 3 B 4Α A 4Β C 5Α A 5Β C 6 A 7 B 8 A 9 B 10 B 11Α A 11B B 12A A 12B B 13 A 14 A 15 A 16 A 17 A 18 B 19 A 20 A 21 A 114619.doc -137- 200808735 BACE-l Example Number IC5〇μΜ

22 Β 23 Β 24 Β 25 A 26 Β 27 A 28 A 29 Β 30 A 31 Β 32 Β 33 A 34 Β 35 Β 36 Β 37 A 38 A 39 Β 40 A 41 A 42 A 43 A 44 A 45 A 46 A 47 A 48 A 114619.doc -138 200808735 BACE-l Example number IC5〇μΜ

49 A 50 Β 51 Β 52 C 53 A 54 A 55 C 56 Β 57 A 58 Β 59 A 60 — 61 A 62 B 63 A 64 A 65 B 66 A 67 A 68 B 69 B 70 A 79 Α A 81 A 97 B 98 B 99 B 114619.doc -139- 200808735 BACE-l Example number IC5〇μΜ

100 Β 101 Β 102 Β 103 CB 104 Β 105 Β 106 Β 107 Β 108 C 109 A 110 Β 111 A 112 Β 113 A 114 A 115 A 116 A 118 -- 119 — 120 A 121 A 122 C 123 B 124 A 125 — 126 A 127 C 114619.doc -140 200808735 BACE-l Example Number IC5〇μΜ

128 C 129 A 130 C 131 A 132 B 133 A 134 A 135 A 136 C 137 A 138 A 139 A 140 A 141 A 142 A 143 A 144 A 145 A 146 B 147 B 148 C 149 B 150 A 151 A 152 A 153 A 154 A 114619.doc -141 200808735 BACE-l Example number IC5〇μΜ

155 A 156 Β 157 Β 158 Β 159 A 160 Β 161 Β 162 Β 163 C 164 A 165 C 166 A 167 168 168 A 169 — 170 A 171 — 172 173 A 174 A 175 B 176 B 177 B 178 B 179 C 180 B 181 C 114619.doc -142- 200808735 BACE-l Example Number IC5〇μΜ 182 A 183 Β 184 Β 185 C 186 C 187 Β 114619.doc -143-

Claims (1)

200808735 X. Patent application scope: 1. A compound of the following formula I: Wherein Ri and R2 are each independently fluorenyl or alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each group optionally substituted, or &amp; and r2 may form an atom with the attached atom a 5- to 7-membered ring optionally substituted with a hetero atom selected from hydrazine, N or S; R3 is hydrazine or alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, Each group may be substituted as appropriate; R4, R5 and R6 are each independently: Η, _, N 〇 2, CN, COR7, NR10CO2Rn, NR15COR16, 〇R14, NR12R13, S〇nRl7 or alkyl, calcination, dilute , haloalkenyl, fast-radical, cycloalkyl or heterocyclic, each group optionally substituted, or if attached to an adjacent carbon atom, R4 and R5 may form an integral with the atom to which they are attached Two optionally substituted 5- to 7-membered rings selected from hydrazine, N or S heteroatoms; η is 0, 1 or 2; 1 and Rn are each independently Η, NH, or alkyl, haloalkyl , alkoxy 114619.doc 200808735 alkyl, alkenyl, alkynyl, cycloalkyl or aryl, each group optionally substituted; R8 and R9 are each independently hydrazine or alkyl, alkenyl, alkynyl or cycloalkane a group, each group optionally substituted, or Rs and R9 may form, together with the atoms to which they are attached, a 5- to 7-membered ring optionally substituted with a hetero atom selected from Ο, N or S; Ru, 1^4 and Ru are each independently an alkyl group, an alkyl group, an alkyl group, an alkoxyalkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group or an aryl group, and each group may be optionally substituted; Optionally substituted alkyl; and Ri2 and R13 are each independently fluorenyl or alkyl or cycloalkyl, each group optionally substituted by ' or R! 2 and R13 may be taken together with the attached atom to form an additional a 5- to 7-membered ring optionally substituted with a hetero atom of hydrazine, N or S; or a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1 has a center and a heart. 3. The compound of claim 1 or 2, wherein 113 is (: 1-(: 4 alkyl). 4. The compound of claim 3, wherein r3 is methyl. 5. The compound of claim 1 or 2, Wherein R 4 , 115 and 116 are each independently hydrazine, halogen, COR 7 , OR 14 , or each optionally substituted alkyl, haloalkyl, alkoxy, haloalkoxy, alkynyl or cycloalkyl group. The compound of claim 5, wherein R4 is hydrazine, COR7, hydrazine R14 or an optionally substituted alkyl, haloalkyl, alkoxy, alkoxy, alkynyl or a ring hospital. 114619.doc 200808735 7 The compound of claim 1 or 2, wherein the center and the heart are each independently η or halogen. 8. The compound of claim 1 or 2, wherein I is at the 3_ position of the phenyl ring. a compound selected from the group consisting of: (5S)-2-amino-5-[4-(monofluoromethoxy)phenyl]methyl-5(phenyl)-3-dihydro - 4H- miso; (5R)-2-amino-5-[4.(difluorodecyloxy)-phenyl]_3_methyl_5_phenyl·3.5-dihydro-4Η-imi 4-ketone; (5R)-2-amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]_3_methyl-3 ,5-Dihydro-4H-imidazol-4-one; (5S)-2.Amino-5-(3-bromophenyl)-5-[4-(difluoromethoxy)phenyl]_3· Mercapto- 3,5-dihydro·4Η-ϋ米嗤_4·酉同; (5R)-2-amino-5-(3-bromo-4-fluorophenyl)_5-[4-(two Fluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imida-4-_; (5S)-2·amino-5-(3-bromo-4-fluorobenzene (5)-[4-(difluorodecyloxy)phenyl]-3·mercapto-3,5-dihydro-4Η-mouth saliva; (5R)-2·amino-5-[4- (difluoromethoxy)phenyl]_3_methyl_5_(3-propylphenyl)-3,5-di-murine 4Η_ϋ米β sit 4-嗣; (5S)-2-amino group_5- [4-(Difluoromethoxy)phenyl]-3-indolyl-5-(3-propylphenyl)-3,5-diphos-4 Η-u rice 嗤 4 _ gang; 2- Amino 5-[4-(difluoromethoxy)phenyl μ5_[3-(3-fluoropropyl)phenyl]_ 3-methyl-3,5-diaza-411-11 rice bran- 4-amine; 2-amino-5-[4-(monofluoromethoxy)phenyl]-5-[3-(3,3-difluoropropyl)phenyl]-3-methyl-3 ,5-dihydro·4Η-indolizin-4-one; 114619.doc 200808735 2-Amino-5-[4-(difluoromethoxy)phenyl μ5_[3·(4-fluorobutyl) Phenyl]_ 3-mercapto-3,5-dihydro-4H-miso-4-indole; 2-amino-5-[3-(4,'difluorobutyl) Phenyl]_5_[4_(difluoromethoxy)phenyl]-3_methyl_3,5·dihydro-4H-imidazole_4-ketone; 2-amino group_5-[4-(two Fluoromethoxy)phenyl]_5_[3·(2-fluoroethyl)phenyl]_3-methyl_3,5-dihydro·4Η-m-n sitting; 2-amino-5-[3- (2,2-difluoroethyl)phenyl]_5-[4-(difluoromethoxy)phenyl]-3-methyl·3,5·dihydro-4H-amid-4-one; 2 -amino-5-[4-(difluoromethoxy)phenyl]_3_methyl_5_[3·(2,2,2-trifluoroethyl)phenyl]-3,5-dihydrogen _4Η·Miso-4-one; 2-amino-5-[4-(difluorodecyloxy)phenyl]-3_methyl_5_[3_(3,3,3_tri-propyl )benzine]-3,5 _-gas-4 Η-πm β sit _ 4 · S with; 2-amino-5-[4-(difluoromethoxy)phenyl]_3_methyl- 5-[3_(4,4,4_三鼠丁)本基]-3,5 _,—gas-4 Η _17 m sal _ 4 - _ ; (5R)-2-amino-5-( 3-butylphenyl)_5_[4_(difluorodecyloxy)phenyl]_ 3 -methyl-3,5 -di-molyte - 4H_mouth-salt-4-indole; (5S)-2-amine 5--5-(3-butylphenyl)_5_[4_(difluorodecyloxy)phenyl]_ 3 -methyl·3,5-di-mouse- 4H_mouth rice bran_4-_; 2· Amino-5·[4·(difluoromethoxy)phenylmethyl-5-(3-pentylphenyl)-3,5-di -4Η-imidazole-4·» ketone; 2-amino-5-[4-(monofluoromethoxy)phenyl]methyl·5_[3-(2-mercaptobutyl)phenyl]-3, 5-dihydro-4H-u rice bran_4_one; 2-amino-5-(3-but-3-ene-indoleylphenyl)_5_[4-(difluoromethoxy)phenyl] -3· fluorenyl-3,5-dihydro-miso_4•嗣; 114619.doc -4 - 200808735 2-Amino-5-[3-(cyclopropylmethyl)phenyl]_5_[4_ (difluoromethoxy)phenyl]-3-methyl-3,5-one gas-4H-indole 嗤-4- discretion; 3- (3-{2-amino-4-[4-(two Fluoromethoxy)phenylmethyloxo_4.5-dihydro-1Η-imidazole_4_yl}phenyl)propanenitrile; (5R)-2-amino-5-[4-(difluoromethoxy) Phenyl]_3_methyl-5-(3-pent-4-yl-1-ylphenyl)_3,5-dihydro-4H-imidin-4-one; (5S)-2-amine 5-[4-(difluoromethoxy)phenyl]_3_methyl-5-(3-pent-4-en-1-ylphenyl)-3,5-dihydro- 4H-flavor Sal-4-ketone; N-(3-{(4R)-2-amino-4-[4-(difluoromethoxy)phenylmethyl-5-oxo-4,5-dihydro-1H -imidazole-4_yl}phenyl)-2-methoxyacetamide; N-(3-{(4S)-2-amino-4-[4-(difluoromethoxy)phenyl] _Methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}phenyl)-2-methoxy B Amine; (5S)-2-amino-5-[4-(difluoromethoxy)phenyl]_3_methylphenyl-3.5-dihydro-4H-imidazol-4-one; 2-amino -5-[4-(^-fluorodecyloxy)phenyl]_5_[3-(4-pyridin-1-yl-1-yl)phenyl]-3-indolyl-3,5-di Hydrogen-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(4-hydroxybutyl)phenyl]-3-methyl 3-,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3-(5-fluoropentyl) Phenyl]-3-methyl-3,5·dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluorodecyloxy)phenyl]-5-[3- (4-fluorobutyl)phenyl]-3-methyl-3,5-dihydro-4indole-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl &gt;5-[3-(6-Fluorohexyl)phenyl]- 3 monomethyl-3,5-dihydro-4Η-imidazole-4-one; 114619.doc 200808735 2-Amino_5-[4 -(difluoromethoxy)phenyl]_5_[3_('methoxybutyl)phenyl]-3-methyl_3,5-dihydro-4Η·σ米唾_4_one; 2- Amino-5-[4-(difluoromethoxy)phenyl]-5_ρ·[(1ζ)_3-methoxyprop-1-en-1-yl]phenyl-3-methyl-3, 5-dihydro-4Η-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]_5_[ 3-(3-methoxypropyl)phenyl]-3-indolyl-3,5-dihydro-4-indole-myristin-4-one; 2-amino-5-[3-(4,4 -difluorobutyl)phenyl]_5_[4_(difluorodecyloxy)phenyl]-3-methyl-3,5-dihydro-4Η-miso-4·显 I ; 3- {2- Amino-4-[4-(difluoromethoxy)phenyl]_1_methyl-5-oxo_4,5-dihydro-1Η-imidazole-4_yl}*^-propyl decylamine (1Ε)-3-Alkyl-1-enyl 2,5·di-phenylphenylhydrazine; 2-Amino-5-[4-(difluoromethoxy)phenyl]_5_{3_[(2 ·Fluoroethoxy)methyl]phenyl}·3-methyl-3,5-dihydro-4Η-imida-4-one; 2-amino-5-[4-(difluoromethoxy) Phenyl]_3•indenyl_5j3_[(3,3,3_trifluoropropoxy)indolyl]phenyl}·3,5-dihydro·4Η· 米米唾-4 ketone; 2-amine 5-[4-(difluoromethoxy)phenyl b-[3-(methoxyindolyl)phenyl]-3-methyl-3,5-dihydro-4H- miso-4 -ketone; 2_amino-5-[3-(butoxymethyl)phenyl]_5_[4-(difluorodecyloxy)phenyl]-3-methyl-3,5-dihydro-4H _imidazole-4·ketone; 2-amino-5-{3-[(cyclopropyldecyloxy)methyl]phenyl ihong [4_(difluoromethoxy)benyl]-3-methyl -3,5-dihydro-4H-mouth rice bran-4,; 2 amine group 5 [4-(fluorocarbon) Phenyl]_5_[3_(ethoxymethyl)phenyl]-3-methyl-3,5-dihydro·4Η-imidazol-4-one; 2-amino-5-[4-( Difluoromethoxy)phenyl]_3_fluorenyl_5_[3_(propoxy 114619.doc -6 - 200808735 methyl)phenyl]-3,5-dihydro-4H-imidazol-4-one; 2-Aminodifluoromethoxy)phenyl(fluoromethyl)ethoxy]methyl}phenyl)-3-methyl-3,5-dihydro-411_Mimi_4_明; 2 -amino-5-[4-(difluoromethoxy)phenyl]·3_methylco.{3_[(2,2 2 -difluoroethyl)methyl]phenyl}-3,5 -diaza-4Η-flavored saliva_4-g同·2-feyl·5-[4-(difluoromethyllacyl)phenyl]_3_methyl 2 3 3 tetrafluoropropoxy)methyl} Phenyl}_3,5-dihydro-4-indole-imidazole_4__; 4-[4-(difluoromethoxy)phenyl]-4_[3-(3-methoxypropan-2-alkynyl)phenyl 1-Methyl-4,5-dihydro-1H-miso-2-amine; 2-amino-5-[3-(l,4-difluorobutyl)phenyl]_5_[4_( Difluoromethoxy)phenyl]-3-methyl-3,5-diaza-s--4- Ming; 2-amino-5·[4-(difluoromethoxy)phenyl]_5_[3_ (3_Flutonium-3-enyl)phenyl]·3-methyl-3,5-dihydro-4H-imidazole·4-_ ; 2-amino-5-[3-(4,4- Difluorobutyr[3|H)phenyl]_5_[4_(difluoro Oxy)phenyl]-3-methyl-3,5-dihydro-4H-imidin-4-yl; 2-amino 4-['(difluoromethoxy)phenyl]·, methyl _5_[3_(4,4,4-trifluorobutyl)phenyl]_3,5-dihydro-4-indole-imidazol-4-one; 5-(3-{2-amino-4_[4_(two Fluoromethoxy)phenyl]small methyl_5_oxo-4.5-dihydro-1Η-imidazol-4-yl}phenyl)pentanenitrile; 4-(3-{2-amino-4-4_[4_ (二敦methoxy)phenyl]small methyl_5.oxo-4.5-dihydro·1Η-imidazole-4_yl}phenyl)butyronitrile; 2-amino-5-{3-[( 1Ε)-4,4_二a丁]·稀]_基]phenyl b 5[4_(difluoromethoxy)phenyl]-3·methyl_3,5-dihydro-dimethoate_4__ ; 2_Amino·5-[4-(difluoromethoxy)phenyl]_5 cases% by hexyl·4_block·114619.doc -7- 200808735 1-based) benzyl]_3_methyl _ 3,5-dihydro-4H-m-methane-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]_5-{3_[(1e)-6-oxime Hexyl-1-en-1-yl]phenyl}-3-methyl_3,5-dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy) Phenyl]_5_{3_[(1e)-5-methoxypent-1-en-1-yl]phenyl-3-methyl-3,5-dihydro-4H-imidazol-4-one ; 2-amino-5-[4-(difluorodecyloxy)phenyl]_5-{3-[2 -(decyloxymethyl)cyclopropyl]phenyldi-3-mercapto-3,5.dihydro-4H-imidazol-4-one; 2-amino-5-[4-(difluoroantimony) Phenyl]-5-{3-[(1Ε)-5-hydroxypent-1-en-1-yl]phenyl}_3_methyl_3,5-dihydro-4]^-imidazole_ 4-keto; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3_[(1Ε)-3-methoxyprop-1-en-1-yl]phenyl }-3-methyl-3,5-dihydro-4Η-imidazol-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-{3-[( 1Ε)-4-methoxybut-1-en-1-yl]phenyl-3-methyl-3,5·diaza-4Η-mouth m°-4-嗣; 2-amino-5 -['(difluoromethoxy)phenyl]-5-{3-[(1Ε)-4-hydroxybut-1-en-1-yl]phenyl}_3·methyl-3,5-di Hydrogen-4Η-imidazol-4-one; 2-amino-5_[4-(difluoromethoxy)phenyl]-5-{3_[2_(2-methoxyethyl)cyclopropyl]benzene }}-3_methyl·3,5-dihydro-4Η-口米嗤-4- Brewing; ; 2_Amino-5-[4-(difluoromethoxy)phenyl]-5-{3 -[(1Ε)_4_fluorobut-1-en_1_yl]phenyl}-3-mercapto-3,5·dihydro·4Η·imidin-4_one; 2-amino-5_[ 4-(Difluoromethoxy)phenyl]-5-{3_[(1Ε)-5-fluoropent-1-en-1yl]phenyl}_3_methyl·3,5-dihydro- 4Η-imidazole-4-one; 5-(3-B Phenyl) 2 -amino-5-[4-(difluoromethoxy)phenyl]_3_indolyl-3,5-dihydro-4H-imidin-4-one; 2-amino-5 -[4-(difluoromethoxy)phenyl]-5-{4-fluoro-3-[(1Ε)-4-fluoro 114619.doc 200808735 丁-1-细-1_yl] Benkib 3 -Methyl-3,5-dihydro-411-m-?--4-yl; 2-amino-5-[4.(difluoromethoxy)phenylfluoropropan-anthracene-yl) Phenyl]-3-methyl-3,5-dihydro-4H-imida-4-one; 2-amino-5-[4-(difluoromethoxy)phenylhydroxyphenyl)_3• Methyl-3,5·dichloro-4H-flavored saliva-4-oxime; 2amino 5-[4-(monofluoromethoxy)phenyl]_5_[3-(3-fluoropropoxy)phenyl] -3-mercapto-3,5-dihydro_4Η-mouth oxime-4-one; 2-amino-5-[3-(cyclopropylmethoxy)phenyl]_5_[4_(difluoro Methoxy)phenyl]-3-methyl·3,5-dihydro- 4Η·. Rice bran; 2-amino-5-[4-(difluoromethoxy)phenyl]_3_methyl-5-[3_(4,4,4-tris-butoxy)benzyl]-3, 5-dichloro-4Η_miso-4-indole; 2-amino-5-[3-(2,2-fluorofluoro)phenyl]_5_[4-(difluoromethoxy)benzene 3-methyl-3,5-dihydro-4-indole-salt-4-one; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[3_( 4-fluorobutoxy)phenyl]-3-methyl_3,5-dihydro-4-indole-myridine-4-one; 2-amino-5-[4-(difluoromethoxy) Phenyl]_3_methyl_5_[3·(3_phenoxypropyloxy))]-3,5 _ -一风-4 Η -味π坐·4 -嗣; 4-(3- (2-Amino-4-[4-(difluoromethoxy)phenyl); ^methyl·% oxo 4,5-dihydro-1 Η·imidazol-4-yl}phenoxy)butyronitrile ; 2_Amino-5-[4-(difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-tripropoxy)phenyl]-3-methyl-3,5 - dihydro-4 hydrazine-imidazole _4 ketone; 2-amino-5-[3-(but-2-yne-1_yloxy)_4_fluorophenyl]_5_[4_(difluoromethoxy) Phenyl]_3·methyl-3,5-dihydro_4Η-imiline-4-_; 2-amino-5-[4-(difluoromethoxy)phenyl]-5-[4_ Fluorine_3_(4_fluorobutoxy 114619.doc -9- 200808735 base) stupid base]-3_mercapto_3,5_dihydro_4 Η-σ米唆-4-ketone; Amino_5_[3-(2,2-difluoroethoxy)-4-fluorophenyl]-5-[4-(difluorodecyloxy)phenyl ]-3-methyl-3,5-dihydro-4H-isoxazol-4-one; (5R)-2-amino-5-[4-(difluoromethoxy)phenyl]-5- [4-fluoro-3-(3-fluoropropoxy)phenyl]-3-methyl_3,5-dihydro-4Η-imidazol-4-one; (5S)-2-amino-5- [4-(Difluoromethoxy)phenyl]-5-[4-fluoro-3-(3-fluoropropoxy)phenyl]-3.indolyl-3,5-dihydro-4H-imidazole 4-ketone; 2-amino-5·{3-[(4,4-difluorobut-3-en-1-yl)oxy]phenyl}-5-[4-(difluoroantimony) Phenyl]-3-ylindolyl-3,5-dihydro-4-indole-imidazole-4-ketone; (5S)-2-amino-5-[3_(2,2-difluoroethoxy) 4-fluorophenyl]-5-[4-(difluorodecyloxy)benzyl]-3-methyl-3,5-diindole-4H-imidol-4-one; (5R)-2 -amino-5-[3-(2,2-difluoromethoxy)-4-fluorophenyl]-5-[4-(difluoromethyllacyl)phenyl]-3-methyl-3 , 5-dihydro-4H-miso-4-_; 2-amino-5-[4-(difluoromethoxy)phenyl]fluoroethyl)phenyl-3-methyl-3,5- Dinitro-4H-rice-indole; 2-amino-5-[4-(difluorodecyloxy)phenyl; fluoropentyl)phenyl]-3-indolyl-3,5-dihydro -4H-味η坐-4·_ ; 2·amino group 5-[4-(difluoromethoxy)phenyl]_5-[3-(4-fluorobutanyl)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one Amino_5-[3_(but-3-en-1-yloxy)phenyl b-5_[4_(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro_ 411_imidazole-heart_; 2_amino-5-[3-(but-3-en-1-yloxy)_4-fluorophenyl]_5-[4-(difluoromethoxy)benyl] -3-methyl-3,5-monohydro-4H. oleic acid; (5R)-2-amino _5_[3-(but-3-ene-i-yloxy)phenyl b 5 ·[4_(difluoro 114619.doc • 10 - 200808735 methoxy)phenyl]-3-mercapto-3,5-dihydroindole _4-ketone; (5S)-2-amino-5- [3-(But-3-en-1-yloxy)phenyl]_5_[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-mipropene_ 4-ketone; 2-amino- 5-{3·[(4,4-dimethylbutan-3-en-1-yl)oxybu-fluorophenyl b-5-[4-(fluorofluoromethoxy) Phenyl]methyl-3,5-dihydro_4Η·salt-4-one; 2-amino-5-[4-(difluorodecyloxy)phenyl]_5-(4-fluoro _3_penta-4_ene_;!_ylphenyl)-3-methyl-3,5-dihydro-411-imiphate_4-_; 2-amino- 5-(3-butyl- 3-wo-buki_4_fluorophenyl)-5_[4_(difluoromethoxy)phenyl]-3-methyl-3,5- Dihydro·4Η-σ米唾_4-_ ; 3-{2-Amino-4-[4-(difluoromethoxy)phenyl]_1_methyl_5_oxo-4,5_ Hydrogen-1Η-imidazol-4-yl}benzaldehyde; 2_amino-5-[4-(monofluoromethoxy)benyl]-5-[3_(1_pyridinyl-2-fast_ 1 -yl)phenyl]-3-methyl-3,5-dihydro-4indole-imidazole; 2-amino-5-[4-(monofluoroindolyl)phenyl]-5-[3-( 1,4-di-butylbutyridin-2-yl-1-yl)phenyl]-3-methyl-3,5-dihydro-4-indole-imidazole-4-one; (5R)-2-amino-5 -[3-(difluoromethoxy)phenyl]_5·[4_(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-411-mouth 嗤-4-_ ; 2-amino-5-[4-(difluoromethoxy)phenyl]_5_[3-(2,2-diamino-3-oxocyclobutyl)phenyl]-3-methyl · 3,5-dihydro-4Η-imidazole_4-ketone; 2-amino-5-[4-(difluorodecyloxy)phenyl]_3_indolyl-5-[3-(3-oxo Cyclobutyl)benzyl]-3,5-a*gas-4 Η-miso-4 -嗣; 2_amino-5-[4-(diindolyloxy)phenyl&gt;5-[ 3_(3-hydroxycyclobutyl)phenyl]-3-methyl-3,5-dihydro-4Η-miso-4-one; 114619.doc -11 - 200808735 , [3_(3-{2- Amino-4-[4-(difluoromethoxy)phenyl]_1_methyl-5-oxo-4.5-dihydro-1H-mi _4-yl}phenyl)cyclobutyl]acetic acid decyl ester; [3-(3-{2-amino-4-[4.(difluoromethoxy)phenyl]-1-methyl-5- Methoxy·4.5-dihydro-1H-imidazol-4-yl}phenyl)cyclobutylidene]acetate; or a tautomer thereof; stereoisomer thereof; and a pharmaceutically acceptable salt thereof. 10. Use of a compound of formula I according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of a disease or disorder associated with excessive B ACE activity in a patient in need of treatment. 11. The use of claim 10, wherein the disease or disorder is selected from the group consisting of: Alzheimer's disease; cognitive impairment; Down's syndrome; hchwa-d; cognitive decline; Alzheimer's disease ; cerebral amyloid angiopathy; and neurodegenerative disorders. 12. The use of claim 10, wherein the disease or disorder is characterized by the production of amyloid deposits or neurofibrillary tangles. 13. The use of a compound according to any one of claims 1 to 9 for the preparation of a medicament for modulating BACE activity. 14. Use of a compound of formula j according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of Alzheimer's disease in a patient in need of treatment. 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of any one of claims 1 to 9. 114619.doc -12- 200808735 'VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best Chemical formula showing the characteristics of the invention: 114619.doc